CHAPTER 11 Depression

In Webster’s Dictionary, definitions for depression include “a psychoneurotic or psychotic disorder marked especially by sadness, inactivity, difficulty in thinking and concentration, a significant increase or decrease in appetite and time spent sleeping, feelings of dejection and hopelessness, and sometimes suicidal tendencies; a lowering of vitality or functional activity; and a state of feeling sad.” Synonyms include sadness, the blues, dejection, being down in the dumps, gloom, heavyheartedness, melancholy, mournfulness, and unhappiness (Figure 11-1). It is part of the human condition to experience periods of sadness and dejection. Unhappiness with a situation can be a prime motivator for change. However, persistent and prolonged feelings of hopelessness and despair often require medical investigation and appropriate treatment.

Figure 11-1 Persistent depression and feelings of despair can require medical treatment.

(From Freeman L: Mosby’s complementary and alternative medicine: a research-based approach, St. Louis, 2004, Mosby.)

Depression currently ranks fourth among the major causes of disability worldwide, after respiratory infections, perinatal conditions, and human immunodeficiency virus infection/acquired immunodeficiency syndrome.¹ In the United States, depression is the second greatest source of disability among women.² It is relatively straightforward to diagnose a mood disorder in someone who presents to the health care system complaining of being sad, down, or tired; the diagnosis is less clear when a patient reports only somatic symptoms. Although recurrent headache, back pain, stomachache, dizziness, chest pain, and fatigue occur in both depressive and physical illnesses, the possibility of depression is often overlooked. This may be due in part to medical curricula that generally teach medical students to rule out physical disorders before considering a mental disorder. A clinician should consider hypothyroidism, anemia, multiple sclerosis, and other conditions that can cause depression, but it is equally important that he or she consider the diagnosis of depression when an individual presents with chronic somatic symptoms. In many cultures, the reporting of somatic complaints by individuals with depression is common. An international study found that nearly 70% of patients with major depression reported only physical symptoms as the primary reason for consulting a physician.³

Because no definitive biologic marker for depression exists, no biochemical test exists to confirm the diagnosis of depression. The diagnosis is made after a thorough history and physical examination and, if necessary, appropriate laboratory tests to rule out other biochemical imbalances that can cause depressive symptoms (e.g., hypothyroidism).

DSM-IV CRITERIA FOR A MAJOR DEPRESSIVE EPISODE

A. Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is depressed mood or loss of interest or pleasure. Note: Do not include symptoms that are clearly caused by a general medical condition or mood-incongruent delusions or hallucinations.

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful.)

2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day.

3. Significant weight loss when not dieting or weight gain (e.g., a change of >5% of body weight in a month), or decrease or increase in appetite nearly every day.

4. Insomnia or hypersomnia nearly every day.

5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).

6. Fatigue or loss of energy nearly every day.

7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).

8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

B. Exclusion of other causes or symptoms

1. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of function.

2. The symptoms are not a result of the direct physiologic effects of a substance (e.g., a drug of abuse or a medication) or general medical condition (e.g., hypothyroidism).

3. The symptoms are not better accounted for by bereavement.

PATHOPHYSIOLOGY

The pathophysiology of depression remains poorly understood but appears to be a complex interplay of genetics, biochemistry, and developmental and social factors. Traumatic events in childhood such as physical or sexual abuse can increase the risk for depression in adulthood ⁴ and a recent stressful event often precedes a depressive episode in a vulnerable individual.⁵ With advances in decoding the human genome, genetic polymorphisms and their role in depression are being explored. For many years, however, a substantial amount of research has been focused on the role of monoamine transmitters in mood disorders.

Although disturbances in norepinephrine and serotonin levels have been repeatedly demonstrated in models of depression, it remains unclear whether these disturbances are the cause of depression or an effect of it. Many biochemical abnormalities have been identified in individuals with depression, among them increased production and release of corticotropin-releasing factor (CRF), which results in abnormalities in hypothalamic pituitary adrenal axis activity. Disruption of glutamate, γ-aminobutyric acid (GABA), growth hormone, and thyroid hormone levels has also been demonstrated, as have abnormalities in secondary messenger systems such as cyclic adenosine monophosphate (AMP).⁶ Activation of secondary messenger systems is important in the maintenance of healthy levels of neurotrophic factors, including brain-derived neurotrophic factor.⁷ An increase in expression of brain-derived neurotrophic factor appears to facilitate both neuronal survival and neurogenesis. Some antidepressant medications may work through this proposed mechanism.

It may be far too simple to assume that depression is simply the result of disruption in monoamine transmitter levels. Treatment failure, in addition to nonadherence with therapy, may be due to our inability to accurately identify subgroups of patients with depression and to provide treatments specifically targeted to their unique neurobiologic characteristics.

TREATMENT

Psychotherapy

An article in the Journal of the Medical American Association reported that between 1987 and 1998, the number of Americans being treated for depression increased from 1.7 million to 6.3 million. The proportion of depressed people taking antidepressants increased from 37% to 75%, whereas the number undergoing psychotherapy decreased from 71% to 60%. This change is likely due in part to the improved availability of medications that are better tolerated by patients. The trend of medicating patients without psychotherapy is cause for concern but not altogether surprising in the era of managed care. In many cases primary-care providers are encouraged to prescribe antidepressant drugs but support for mental-health counseling is limited. Most experts are convinced, however, that the majority of patients do best with a combination of medication and psychotherapy. This is especially true in cases of chronic major depression, in which combined treatment has been found significantly superior to medication or psychotherapy alone.⁸

Prescription Medication

Several different classes of antidepressants have been shown to be effective in clinical trials. These include monoamine oxidase (MAO) inhibitors, tricyclic antidepressants (TCAs), selective serotonin-reuptake inhibitors (SSRIs), and novel agents including serotonin- and norepinephrine-reuptake inhibitors (SNRIs). Current treatments often produce only partial symptomatic improvement (response) rather than symptom resolution and optimal function (remission). Some new agents, including CRF antagonists, substance P antagonists, and antiglucocorticoids, hold promise in the refinement of treatment options, especially among subgroups of patients who do not fully respond to first-line treatments.⁹

Debate continues over the differences in efficacy and tolerability among the different classes of antidepressant drugs. A systematic review of 108 metaanalyses of antidepressant medications revealed the following: only small differences in efficacy exist between most new and old antidepressants (old being defined as those on the market before the 1980s); superior efficacy of SNRIs over SSRIs; slower onset of therapeutic action of fluoxetine compared to other SSRIs; superior general tolerability of SSRIs over TCAs; poorer tolerability of fluvoxamine than of other SSRIs in a within-group comparison; and no increase in the risk of suicidal acts or ideation with fluoxetine compared with TCAs (or placebo) in low-risk patients.¹⁰

Serotonin is a major player in mood, whereas norepinephrine is involved in drive and energy state. There is interaction between them in matters of appetite, sleep regulation, and anxiety. It is generally accepted that depletion of serotonin is related to depressive symptoms. A strong link also exists between stress and depression. Stress systems in the brain are, for the most part, mediated by norepinephrine transmission.

One hypothesis holds that dual-action antidepressant drugs such as venlafaxine and milnacipran are superior in efficacy to those that mainly affect the serotonergic pathway. Some research is available to support this hypothesis. A recent metaanalysis showed that venlafaxine had greater efficacy than SSRIs in the treatment of depression.¹¹ Venlafaxine is also being promoted as a treatment for menopausal flushing, especially in women who cannot or prefer not to take estrogen replacement therapy (ERT; see Chapter 6).

In addition to relieving the symptoms of depression, substances that modulate both the serotonin and norepinephrine (NE) pathways can be helpful to patients with pain. Both serotonin and NE neural circuits directly modulate the descending pathways and make up an integral part of the complex system that controls pain perception.¹² The TCAs have been shown clinically to reduce pain; however, their side effect profile often limits their use in general practice. The SNRIs may prove a useful tool in patients with chronic pain or the dual diagnosis of pain and depression. The authors of one study found that extended-release venlafaxine at a dosage of 150 to 220 mg/day was significantly better than placebo in relieving diabetic neuropathic pain by the third week of treatment.¹³

Estrogen Replacement Therapy

Many practitioners believe that ERT improves mood in perimenopausal and menopausal women, but current research neither validates nor disproves this assertion. Although neurobiological studies show promising antidepressant effects of estradiol on serotonergic, noradrenergic, cholinergic, dopaminergic, and GABA-ergic functions, no consistent findings of a correlation between any serum hormone level and the severity or presence of depressive symptoms have been reported. Most clinical trials have shown a modest effect on symptoms of depression; however, the methodologic limitations of the research do not permit generalization or recommendations.¹⁴ Given concerns with long-term use of ERT (see Chapter 6), more definitive information is needed.

Integrative Approaches

Any truly integrative approach to the treatment of depression should include investigation of the patient’s physical and emotional well-being, as well as a careful examination of lifestyle. Stress reduction is an important part of the wellness strategy for anyone with depression. Relaxation, meditation, yoga, prayer, and journal-keeping can all be effective tools in helping reduce stress and create a sense of empowerment in the patient. Research suggests that regular exercise improves mood.¹⁵ The clinician should discuss and encourage healthy dietary habits, including a reduction in the consumption of caffeinated beverages, especially if the patient is feeling anxious or not sleeping well, and the limitation of alcohol-containing beverages to one per day.

Supplements and Botanicals

Omega-3 fatty acids.

A growing body of evidence demonstrates the many health benefits of fish oil. Intervention trials in human subjects show that omega-3 fatty acids may have positive effects in the treatment of various psychiatric disorders.¹⁶ The findings of epidemiologic surveys indicate that populations consuming large amounts of fish have lower rates of depression than do members of groups that consume small amounts.¹⁷ Research indicates that individuals with major depression have marked depletions in omega-3 fatty acids (especially docosahexaenoic acid [DHA]) in erythrocyte phospholipids compared with controls.¹⁸ Arachidonic acid and DHA account for roughly half of total brain phospholipids, substances necessary for the proper function of the nerve-cell membranes and second messenger systems believed to play a role in depression and other mood disorders.

Although epidemiologic and basic-science studies suggest that long-chain fatty acids are beneficial for individuals prone to or experiencing depression, well-controlled clinical trials are needed. To date, only two double-blind studies have been completed. Four weeks of supplementation with 2 g/day of eicosapentaenoic acid ethyl ester (E-EPA) enhanced the antidepressant effects of conventional drug therapy in a double-blind, placebo-controlled study of 20 patients with recurrent unipolar depressive disorder treated with maintenance antidepressant therapy. The 24-item Hamilton Rating Scale for Depression (HAM-D) was administered at baseline and weekly thereafter. The average HAM-D baseline score was 18 or less. By the end of the study, E-EPA–treated patients showed a mean reduction of 12.4 points, compared with a mean reduction of 1.6 points among patients receiving a placebo. The researchers were unsure whether E-EPA augments the effect of the antidepressant therapy by way of the secondary messenger system or whether it exerts an independent antidepressant effect.¹⁹ A 12-week randomized, double-blind, placebo-controlled study of 60 patients with persistent depression who were taking conventional antidepressant drugs found that 1 g/day of E-EPA improved depression scores more than did placebo. Higher doses of 2 g/day or 4 g/day did not lead to further improvement.²⁰

Given the relatively inexpensive cost of omega-3 fatty-acid capsules, the other health benefits of omega-3, and the very low side-effect profile, patients with depression may wish to add fish to the diet twice a week or supplement the diet with omega-3 capsules. Quality control of fish-oil capsules has been a concern as fish can accumulate toxins such as mercury, dioxins, and polychlorinated biphenyls. Neither the Food and Drug Administration (FDA) nor any other federal or state agency tests fish oil supplements for quality before sale. Consumer Labs tested 20 fish oil products and found that none contained any detectable level of mercury; however, six of the 20 products failed to pass review because they contained inadequate amounts of DHA ranging from just 50% to 83% of the amounts stated on the labels.²¹ Although the optimal dose has not yet been determined, most authorities recommend 1 to 3 g/day of omega-3 fatty acids.

SAMe.

S-adenosyl-L-methionine (SAMe), derived from the sulfur-containing amino acid methionine and adenosine triphosphate (ATP), is a natural substance that plays an important role in many of the body’s biochemical processes. SAMe is the most important methyl donor in transmethylation reactions occurring in the central nervous system. Serum and cerebrospinal-fluid levels of SAMe are reported to be low in some patients with depression.

The Agency for Healthcare Research and Quality published a review of the evidence on SAMe in the treatment of depression, osteoarthritis, and liver disease. Of 39 studies considered, 28 were included in a metaanalysis of the efficacy of SAMe in reducing symptoms of depression.²² Reviewers found that SAMe was superior to placebo. Compared with treatment with conventional antidepressant drugs, SAMe was not associated with a statistically significant difference in outcome.

This dietary supplement must be taken as an enteric-coated tablet in the morning, before breakfast. The dosage used to treat depression generally ranges from 400 to 1200 mg/day. The patient should be instructed to start with 400 mg/day for 5 days and then increase the dosage by 200 mg/day every 3 to 5 days as needed. The main side effects are gastrointestinal upset, nausea, agitation, and insomnia. Taking the supplement with food will reduce the incidence of gastrointestinal complaints. Agitation and insomnia are often dosage-related. SAMe is contraindicated in patients with bipolar disorder as it can induce mania.

St. John’s wort (Hypericum perforatum).

St. John’s wort is the most heavily studied botanicals for depression. Its use as a mood-elevating substance may date back 2000 years or more. H. perforatum, meaning “over an apparition,” is the botanical name given by the ancient physician Dioscorides (70 CE). The name was apparently chosen because the plant was believed to protect the user from evil or wandering spirits. It is quite possible that early users of St. John’s wort found that the herb “lifted” the spirits (or eased depression). Early Christians, noting the red oil glands on the plant’s leaves, claimed that they represented the blood spilled by John the Baptist during his beheading and gave the herb its common name, St. John’s wort. Others say the common name is derived from the fact that the herb blooms on St. John’s Day (Figure 11-2).

Figure 11-2 St. John’s Wort (Hypericum perforatum).

(Courtesy Martin Wall Botanical Services.)

A 1996 metaanalysis of St. John’s wort in the British Medical Journal²³ revealed that St. John’s wort is more effective than placebo in the treatment of mild to moderate depression. This review helped focus attention on this herb in the United States, and sales quickly increased. Sales remained high until 1998-1999, when reports of herb-drug interactions began to be reported in the media. By the spring of 2002, results from 34 controlled double-blind trials of Hypericum extracts in some 3000 patients, mostly with mild to moderate depression, had been published.²⁴

The most recent Cochrane review found 27 trials with a total of 2291 patients that met inclusion criteria for a metaanalysis. Seventeen trials with 1168 patients were placebo-controlled (16 trials involved monopreparations and one involved St. John’s wort plus four other herbs), and 10 trials (eight single preparations and two combinations of St. John’s wort and valerian) with 1123 patients compared Hypericum with other antidepressant or sedative drugs. Most trials lasted 4 to 6 weeks, and the diagnosis in most participants was “neurotic depression” or “mild to moderate severe depressive disorder.” The authors concluded, “There is evidence that extracts of Hypericum are more effective than placebo for the short-term treatment of mild to moderately severe depressive disorders. The current evidence is inadequate to establish whether Hypericum is as effective as other antidepressants. Further studies comparing Hypericum with standard antidepressants in well defined groups of patients over longer observation periods, investigating long-term side effects, and comparing different extracts and doses are needed.”²⁵

Another meta-analysis of 22 randomized, controlled trials showed St. John’s wort to be significantly more effective than placebo (relative risk 1.98) and not significantly different in efficacy from other antidepressant agents (relative risk 1.0). Adverse effects occurred more frequently with standard antidepressants than with St. John’s wort.²⁶ At the time of this writing, on the basis of the existing data, it appears that St. John’s wort is superior to placebo in the treatment of mild to moderately severe depression. Equivalency, or superiority, to conventional antidepressants has not been adequately addressed, although the Whiskey metaanalysis suggests that St. John’s wort is not significantly different from prescription medication.

The vast majority of studies have demonstrated that St. John’s wort extract is superior to placebo in the treatment of depression, with the notable exception of two studies published in the Journal of the Medical Association. The first of these trials was published in 2001. A randomized, double-blind, placebo-controlled clinical trial was conducted in 200 patients with major depression and a baseline HAM-D score of at least 20. After a 1-week single-blind run-in of placebo, participants were randomized to receive either 900 mg/day St. John’s wort extract (0.3% hypericin) or placebo for 4 weeks. The dose could be increased to 1200 mg/day for the remainder of the 8-week study if treatment response was inadequte. Response rates in the intention-to-treat analysis were not significantly different between the two groups: 26.5% for St. John’s wort and 18.6% for placebo. The number of participants achieving remission of symptoms was significantly higher with St. John’s wort than with placebo (P = 0.02), but the rates were low in the full intention-to-treat analysis (14.3% and 4.9%, respectively). The authors conclude, “These results do not support significant antidepressant or antianxiety effects for St. John’s wort when contrasted with placebo in a clinical sample of depressed patients.”²⁷ The study was challenged for its lack of a historical active, study population of severely depressed patients and its very low placebo response, an uncommon finding in antidepressant trials, where placebo response is generally 25% to 30%.

The National Institutes of Health–sponsored study is the longest and most rigorous study of St. John’s wort conducted so far.²⁸ Three hundred forty moderately to severely depressed patients were randomly assigned to receive St. John’s wort extract, placebo, or sertraline for 8 weeks. On the basis of clinical response, the daily dose of St. John’s wort extract could range from 900 to 1500 mg and sertraline from 50 to 100 mg. Patients who demonstrated a response at week 8 could continue their blinded treatment for an additional 18 weeks. The two primary outcomes were change in the HAM-D between baseline and 8 weeks and the rates of full response (as determined by changes in HAM-D and Clinical Global Impressions scores). With regard to change in the HAM-D score, neither sertraline nor St. John’s wort extract was statistically different from placebo. Full response occurred in 31.9% of the placebo-treated patients, compared with 23.9% of the St. John’s wort extract–treated patients (P = 0.21) and 24.8% of the sertraline-treated patients (P = 0.26). Neither sertraline nor St. John’s wort extract performed as well as placebo with regard to this primary outcome. Sertraline was better than placebo on the Clinical Global Impressions improvement scale (P = 0.02), which was used as a secondary measure in this study.

The media reports, based on the findings of this trial, that St. John’s wort is ineffective in the treatment of major depressive disorder, do not provide an entirely accurate picture. In studies of antidepressants, the tested drug often fails to do better than placebo. This is a result of both the high subjectivity of the scales used and the typically large placebo response. A review of clinical-trial data from the nine antidepressants approved by the FDA between 1985 and 2000 included 10,030 patients with depression who participated in 52 antidepressant clinical trials evaluating 93 treatment arms. The researchers found that fewer than half (48%, 45 of 93) of the antidepressant-treatment arms showed superiority to placebo.²⁹ To avoid a false-negative result (type II error), antidepressant trials would have to involve 300 or more patients per arm; otherwise, more sensitive research designs must be developed.³⁰ The appropriate conclusion from this trial is that it was not sensitive enough to detect the effectiveness of either sertraline or St. John’s wort extract or that this was primarily a group of “nonresponders.”