Depression

CHAPTER 5

Depression Craig Schneider, MD  •  Theodore Wissink, MD

Centers for Disease Control and Prevention surveys indicate that nearly 1 in 10 residents of the United States who is 18 years old or older has a depressive disorder.1 Annual prevalence rates in patients with chronic disease are about 25%.2 In fact, depression is one of the chronic conditions for which alternative therapies are most frequently used.3 This statistic is not surprising considering that pharmaceutical antidepressant medications are not as effective as once believed for many patients with less severe forms of depression.4 Many people seen in primary care settings fall under the DSM-5 category “persistent depressive disorder.” The Patient Health Questionnaire-2 (PHQ-2) can be used for screening,5 and the longer Patient Health Questionnaire (PHQ-9) (see Key Web Resources, later) can be used both for diagnosis and tracking of depression treatment outcomes in the primary care setting.6 Clinicians should discuss the spectrum of treatment options including antidepressant medications and/or psychotherapy and integrative medicine treatments.7

PATHOPHYSIOLOGY The pathophysiology of depression is not fully understood. The stress–diathesis model of illness emphasizes that significant emotional, social, and environmental antecedents such as the loss of a family member or a romantic or professional disappointment, as well as genetic and acquired vulnerabilities, are clearly involved. Significant stressors appear to be more frequently involved with initial episodes. In recurrent depression, vulnerability appears to increase as episodes become less and less related to stress and more autonomous in a process known as kindling.8,9 With repeated episodes of illness (kindling), central nervous system dysfunction increases, as manifested by hypercortisolemia, decreased slow-wave (restful) sleep, and increased rapid eye movement (arousing) sleep and disruption of neuroplasticity.10 Inflammation is now considered another important mediator. High levels of inflammatory biomarkers are found in depressed patients and improve as symptoms resolve.11 The biochemical impact of depression may be stored in neurons through changes in the activity of gene transcription factors and neuronal growth factors.12 A common final pathway is the biochemical imbalance of biogenic amines or neurotransmitters (e.g., serotonin, norepinephrine, gamma-aminobutyric acid [GABA], and dopamine) and their relationships with their respective receptors in the brain. Potential effects on neurotransmitters include impaired synthesis, increased breakdown, and increased pump uptake, with consequent alterations in neurotransmitter levels. This increasingly sophisticated understanding of the underpinnings of 36

depression may one day lead to improved treatment, but for now pharmaceutical approaches to treating depression involve correction of altered neurotransmitter levels and of neurotransmitter receptor interactions.

INTEGRATIVE THERAPY Exercise as Medicine More than 1000 trials have examined the relationship between exercise and depression, and most have demonstrated an inverse relationship between them.13,14 Physical activity may also prevent the initial onset of depression.15,16 Regularly performed exercise is as effective an antidepressant as psychotherapy or pharmaceutical approaches.13,17–21 Well-designed studies also support that exercise combined with pharmacologic treatment is superior to either alone, but exercise appears to be superior in maintaining therapeutic benefit and preventing recurrence of depression.22–26 Evidence provides some support for the use of exercise. A recent Cochrane review (updated from 2009) included 32 studies (n = 1858) involving exercise for the treatment of researcher-defined depression. From these studies, 28 randomized controlled trials (RCTs) (n = 1101) were included in a meta-analysis revealing a moderate to large effect in favor of exercise over standard treatment or control. However, only four trials (n = 326) with adequate allocation concealment, blinding, and ITT analysis were found, resulting in a more modest effect size in favor of exercise. Pooled data from seven trials (n = 373) with long-term follow-up data also found a small clinical effect in favor of exercise.28 The additional benefits that may be attained by patients who exercise, including increased self-esteem, increased level of fitness, and reduced risk of relapse, make exercise an ideal intervention for patients suffering from depression. Both aerobic and anaerobic activities are effective.19,23,33,34 Regardless of the type of exercise, the total energy expenditure appears more important than the number of times a week a person exercises, and highenergy exercises are superior to low-energy exercises.

Exercise to Prevent Pregnancy-Related Depression According to recommendations from both the American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and Gynaecologists, pregnant women without medical contraindications should engage in regular aerobic and strength-conditioning exercise during the perinatal period.29 A study of prenatal aerobic exercise in women without depression has shown that exercise or physical activity was associated with fewer depressive

5  Depression

symptoms in pregnancy.30 Few controlled studies have evaluated the effectiveness of exercise as a treatment for postpartum depression. Two RCTs comparing a 12-week intervention of exercise to a control situation in postnatal depression symptoms demonstrated a significantly greater reduction in these symptoms with exercise as compared to controls.31,32 Based on this small number of studies, we recommend the following for the general health of perinatal patients: 30 minutes of exercise per day, most days of the week, in the absence of either medical or obstetric complications and after consultation with a physician. Exactly why exercise relieves or prevents depression is not understood. Although exercise may increase levels of serotonin, norepinephrine, and endorphins, its benefits have been reported even when naloxone is administered to block endorphins. Exercise may also increase nerve cell growth in the area of brain that modulates mood, similar to pharmaceuticals.35,36 Exercise is inexpensive, has proven benefits beyond the treatment of depression, has a low occurrence of side effects, and is available to everyone. The appropriate exercise prescription depends on the specific patient’s health, motivation, level of fitness, and interests (see Chapter 91, Writing an Exercise Prescription). For more seriously depressed patients and those with significant psychomotor retardation, the exercise regimen should be started as adjunct therapy. Write an exercise prescription for all patients; tailor the type of exercise to something the patient enjoys, whether aerobic or anaerobic.

NUTRITION Caffeine and Simple Sugars Cross-national epidemiologic studies suggest a correlation between sugar intake and rates of major depressive disorders.37 Examination of the diets of people suffering from depression reveals increased consumption of sucrose compared with the general population.38 A small cohort trial found that eliminating refined sucrose and caffeine from the diets of people experiencing unexplained depression resulted in improvements by 1 week, and symptoms worsened when patients were challenged with these substances but not with placebo.39 However, protective effects in women of drinking 2 to 5 cups of coffee daily have been demonstrated,40 and an inverse relationship appears to exist between daily tea drinking and depression.41 At this point, no clear cause and effect has been demonstrated.

Dietary Patterns Prospective data suggest a protective effect of a whole foods traditional diet (vegetables, fruit, beef, lamb, fish, and whole grains) or Mediterranean-style diet (omega-3 fatty acids [from fish], monounsaturated fatty acids [from olive oil], and natural folate and other B vitamins [from legumes, fruit and nuts, and vegetables]) versus a Western-style diet (high levels of energy, saturated fats, and refined sugar, as well as fried and highly processed foods)42 across a number of populations (British, Australian, Spanish, Korean) after adjusting for potential confounders.43–46 At this point, no

37

large, high-quality clinical trials have been published supporting the use of diet for treating depression (although one is underway),47 but the evolving understanding of the underpinnings of depression, including inflammation, suggest a rationale for dietary manipulation in treatment.

Alcohol A systematic review confirmed that alcohol-related problems are more common in depressed individuals than in the general population and are associated with worse outcomes.48 Although consumption of alcohol transiently increases the turnover of serotonin, the long-term result is diminished levels of serotonin and catecholamines.49 Elimination of alcohol intake appeared to reduce depressive symptoms in a number of studies.42 Because of the safety, potential health benefits in other areas, and low cost of this intervention, limiting alcohol consumption is warranted. Recommend that patients adhere to a traditional or Mediterranean dietary pattern and limit sugar and alcohol consumption.

Omega-3 Fatty Acids Epidemiologic data suggest that a deficiency of omega-3 fatty acids or an imbalance in the ratio of omega-6 and omega-3 fatty acids correlates positively with increased rates of depression.50 Because dietary polyunsaturated fatty acids and cholesterol are the major determinants of membrane fluidity in synaptic membranes involved in the synthesis, binding, and uptake of neurotransmitters, it is hypothesized that alterations may lead to abnormalities contributing to increased rates of depression.51 Although the current evidence does not support using omega-3 fatty acids as monotherapy to treat depression,52 small, welldesigned studies support the use of omega-3 fatty acids as adjuncts to conventional antidepressant therapy.53,54 Preliminary evidence also suggests that children with depression and women with depression during pregnancy may benefit from supplementation with omega-3 fatty acids.55,56 A recent meta-analysis suggests omega-3 supplements containing 60% or more eicosapentaenoic acid (EPA), with a ceiling of 2000 mg of EPA in excess of docosahexaenoic acid (DHA), appears to be most effective.57 Consumption of two or three servings each week of smaller cold-water fish (herring, mackerel, wild salmon, sardine) may be comparable. One caveat to consider is the issue of heavy metal and pesticide contamination of available seafood and supplemental fatty acids. Larger fish and some farmed fish may bioconcentrate toxins, including mercury and polychlorinated biphenyls. Vegetarian alternatives to consider include flaxseed oil or ground flaxseed meal (2 tablespoons daily) and a small handful of walnuts each day, but these substances have not been studied with respect to depression (see Chapter 88, The Antiinflammatory Diet). The role of docosahexaenoic acid is generally more structural (important for brain and retina development), while that of eicosapentaenoic acid is generally more functional (improves communication across cell membranes).

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PART II  Integrative Approach to Disease

DIETARY SUPPLEMENTS Vitamin D Epidemiological evidence shows that Vitamin D deficiency is associated with an 8% to 14% increase in depression.58–60 However, causality and efficacy of supplementation remain controversial awaiting confirmation by systematic review and meta-analysis. These reviews have produced conflicting results but include studies with many different designs and flaws (e.g., ineffective interventions that failed to increase or actually decreased 25OHD [25-hydroxy vitamin D] levels or failed to measure a baseline 25OHD level). A recent meta-analysis that included only studies without such flaws found a statically significant effect of vitamin D supplementation on depression scores, comparable to the magnitude of the effect of typical antidepressant medications.61 These results are promising, but clearly, more studies are needed to make a more definitive statement on the effectiveness of Vitamin D supplementation on depression.

B Vitamins Folic acid and vitamin B12 are intimately linked with the synthesis of S-adenosylmethionine (SAMe), and each functions as a methyl donor, carrying and donating methyl groups to a variety of brain chemicals, including neurotransmitters. Although large-scale clinical studies are lacking, a trial of a B-complex vitamin is advisable, particularly for older patients, in whom B12 deficiency is common, and for persons with suboptimal diets. Vitamin B6 is essential in the manufacture of serotonin, and vitamin B6 levels have been found to be low in many depressed patients, particularly in premenopausal women taking oral contraceptive pills or replacement estrogen.25,50,62 Dosage

One B-complex vitamin daily. A B-50 has approximately 50 mcg or mg of most of the B vitamins, and a B-100 has about 100 mcg or mg. Both are safe. The one B-vitamin that can be neurotoxic at doses > 200 mg daily is B6 (pyridoxine).

Dosage

400 mcg to 1 mg daily (although doses of 5 to 20 mg daily have been used in studies). Consider L-methylfolate 7.5 to 15 mg, which may be better tolerated. Precautions

High doses of folic acid have been reported to cause altered sleep patterns, vivid dreaming, irritability, exacerbation of seizure frequency, gastrointestinal disturbances, and a bitter taste in the mouth, and concerns have emerged about possible increased risk of some cancers.

S-Adenosylmethionine

SAMe (Fig. 5.1) is the major methyl donor in the body and is involved in the metabolism of norepinephrine, dopamine, and serotonin. Its synthesis is impaired in depression, and supplementation results in increased brain monoamine levels, enhanced binding of neurotransmitters to receptors, and increased brain cell-membrane fluidity. Although larger trials are warranted, multiple open and RCTs suggest that SAMe is an effective natural antidepressant. An RCT comparing SAMe (1600 mg orally, daily) with imipramine (150 mg orally, daily) over 6 weeks demonstrated equivalent efficacy and superior tolerability of SAMe.67 Another small, double-blind, placebo-controlled trial of SSRI nonresponders with major depression compared adjunctive SAMe (800 mg orally, twice daily) with placebo and found SAMe significantly more likely to lead to remission.68 A more recent RCT from 2014 compared SAMe, escitalopram, and placebo and showed similar significant improvement in depression for all three treatments after 12 weeks.69 An agency for Healthcare Research and Quality evidence report and technology assessment in 2002 found SAMe to be superior to placebo and comparable to conventional antidepressants, based on available evidence. SAMe is generally well-tolerated and has a more rapid onset of action than that of standard pharmaceutical antidepressants.70 Because of this characteristic, some clinicians start SAMe

Folic Acid Up to one-third of depressed adults have borderline or low folate levels. A subgroup of depressed patients with folate deficiency and impaired methylation and monoamine neurotransmitter metabolism has been identified.63 In fact, depression is the most common symptom of folate deficiency.64 Patients with low levels of folate also appear to respond more poorly to therapy with selective serotonin reuptake inhibitors (SSRIs).67 Limited evidence from a Cochrane Review suggests that the addition of folate to conventional antidepressant therapy is beneficial.65 More recent trials have used L-methylfolate, the active and more bioavailable form of folic acid.66 Folate may also have other health benefits (e.g., prevention of neural tube defects and reduction of elevated homocysteine). Supplementation with vitamin B12 concomitantly makes sense to avoid masking a deficiency (see Chapter 38, MTHFR Mutation).

Methionine

SAMe synthase

Vitamin B12 CH3-folate

SAMe

ATP CH3

S-Adenosyl homocysteine Adenosine

ATP

Homocysteine FIG. 5.1  □  S-Adenosylmethionine (SAMe) metabolism. SAMe may cause hypomania or mania in patients with bipolar disease and should be avoided in this population. ATP, adenosine triphosphate; CH3, methyl group.

5  Depression

concurrently with another dietary supplement or pharmaceutical approach to therapy of depression that has been more thoroughly studied and then taper the dose of SAMe to zero as the other antidepressant begins to take effect. The most stable and bioavailable oral form appears to be 1,4-butane-disulfonate (Actimet), which is stable for up to 2 years at room temperature. SAMe does not have known cardiac, anticholinergic, or orthostatic effects. Larger clinical trials comparing SAMe with placebo and standard of care will help elucidate its role in treating depression. Dosage

Initial treatment of depression may require 1600 mg daily given in two equal doses. We recommend starting with 200 mg once or twice daily followed by slow titration up over 2 weeks to minimize gastrointestinal side effects. Precautions

High dosages can cause nausea, vomiting, flatulence, and diarrhea. Avoid giving the second dose close to bedtime because it can cause insomnia.

39

dopamine, norepinephrine, and GABA reuptake inhibition and also in vitro monoamine oxidase inhibition and l-glutamate.67 SJW also appears to inhibit interleukin-6 and increase cortisol production, which may result in an additional indirect antidepressant effect.75 Clinical effects are probably the result of a combined contribution of multiple mechanisms, each individually too weak to account for the action.76 SJW has been a licensed prescription medication in Germany since 1984, and nearly twice the number of prescriptions are written for it as for all other antidepressants in that country. Two large US trials found that SJW was not effective for treating severe major depression.77 The most recent Cochrane Reviews examined the findings of 29 trials (nearly 5500 patients) comparing SJW with placebo or standard antidepressants and concluded that available evidence suggests that SJW is superior to placebo and is as effective as conventional antidepressants and better tolerated.78 Large-scale postmarketing surveillance studies of SJW extracts (14,245 patients) recorded rates of adverse effects 10-fold lower than for conventional antidepressants.79 Indication SWJ is indicated for mild to moderate depression.

Hydroxytryptophan Hydroxytryptophan (5-HTP) is the intermediate in the metabolism of tryptophan to serotonin. Open trials and RCTs have suggested that 5-HTP is as effective as standard antidepressants.71,72 A Cochrane Review found only 2 of 108 trials of sufficient quality for inclusion, but in these trials, 5-HTP was superior to placebo.73 Tryptophan itself appeared promising as a treatment for insomnia and depression but was removed from the market (although it is available again) when a contaminated batch was linked to an outbreak of eosinophilia myalgia syndrome in people with abnormal activation of the kynurenin pathway. Although 5-HTP is not metabolized along this pathway, case reports link 5-HTP to an illness resembling eosinophilia myalgia syndrome. The suspected culprit is a family of contaminants known as peak X that is commonly found in commercially available 5-HTP.74 Because uncertainty surrounding 5-HTP remains, it seems advisable to avoid recommending its use pending further information. Case reports of seizures in Down syndrome and dermatomyositis in conjunction with the use of carbidopa have appeared in the literature. Use with other serotonin agonists is not recommended, to avoid serotonin syndrome. Dosage

5-HTP 50-200 mg three times daily. We recommend starting with 50 mg and titrating up over a few weeks if needed.

BOTANICALS St. John’s Wort (Hypericum perforatum) The exact mechanism of action of St. John’s wort (SJW) remains unknown, but this botanical affects serotonin,

Dosage

300 mg three times daily has been used most frequently in clinical trials. 450 mg twice daily has also been used. Choose a product standardized to a minimum of 2% to 5% hyperforin or 0.3% hypericin such as those used in clinical trials. Examples include Lichtwer LI 160 found in Kira and WS5572, containing a minimum level of 3% hyperforin found in Perika (Schwabe, Nature’s Way). Once clinical improvement has been obtained, consider twice-daily dosing. Up to 2 months may be required before full effects are noted. Precautions

Although side effects are fewer than with current pharmacologic antidepressants, they can include gastrointestinal upset, allergic reaction, fatigue, dry mouth, restlessness, constipation, sexual side effects, and possibly increased risk of cataracts. St. John’s wort can activate the cytochrome P-450 3A4 detoxification system in the liver, as well as p-glycoprotein, and thereby reduce the serum levels of drugs metabolized by this pathway. Caution should be used in patients receiving antiretroviral, warfarin, cyclosporine, and oral contraceptive therapy.

Saffron In addition to its well-known culinary uses, saffron has long been used in traditional Persian medicine to treat mood disorders. Small, controlled trials now suggest that a specific saffron extract can improve symptoms of depression as effectively as imipramine (100 mg daily) and

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PART II  Integrative Approach to Disease

fluoxetine (20 mg daily) in patients with mild to moderate ­ depression after 6 weeks of treatment and is well-tolerated.80,81 Dosage

30 mg daily (Novin Zaferan Co., Iran) Safety Saffron has “Generally Recognized as Safe (GRAS)” status in the US

MIND–BODY THERAPY Antidepressants and psychotherapy are first-line treatments for depression according to the American Psychiatric Association (APA); even so, only 60% of those treated will have a clinically significant response, and many others may have residual symptoms.82 Many psychotherapies can be considered mind–body approaches. One-fourth of patients with depression have tried some type of mind–body therapy,83,84 and two-thirds of those found it beneficial.84 Depression-specific psychotherapies are designed to provide acute, time-limited interventions. They are present-oriented and pragmatic, focusing on depression and issues considered relevant to both its onset and its perpetuation.85 Primary care physicians can provide limited, supportive psychotherapy at frequent visits necessary to monitor the effectiveness of medications.86 In fact, generic counseling appears to be preferred by patients over antidepressant drugs and is as effective, although slower in onset, for treating mild to moderate depressive illness.87 Cognitive therapy in which the physician or therapist assists the patient in replacing negative patterns of thinking with a more positive and realistic approach is the most-studied psychotherapeutic approach to major depression. Multiple studies have demonstrated the equivalency of this modality to rigorous antidepressant medication regimens.85 Mind–body therapies encourage an active process through which the patient learns from their symptoms versus taking a medication or supplement during which the individual is a passive recipient.

There is an ever-growing diversity of psychotherapeutic approaches including “third wave cognitive behavioral therapies” (e.g., mindfulness-based cognitive therapy, compassionate mind training, acceptance and commitment therapy) and psychodynamic therapies, as well as integrative approaches that combine aspects of various models. However, evidence is lacking as to which psychotherapeutic approach is most effective.87A

Mindfulness-Based Cognitive Therapy Based upon the work of Jon Kabat Zinn’s “Mindfulness Based Stress Reduction,” MBCT focuses on allowing distressing emotions, thoughts, and sensations to come and

go, without grasping onto the need to suppress, fight, or escape them.88 This specific method has been successful for treating depression in a variety of patient populations.89 Several initial studies also demonstrate that MBCT can decrease the recurrence of depression.90–92 MBCT appears to be particularly effective in patients who have had three or more relapses and may be equal to medication in preventing relapse in this difficult-to-treat population.

Other Mind–Body Therapies Yoga Yoga is rooted in Indian philosophy and has become a popular route in Western culture towards improving physical and mental well-being. Yoga is most often associated with physical postures, breath control, and meditation. Different yoga schools have emerged that put varying degrees of focus on the physical and meditation practices. A recent systematic review located 12 RCTs (pooled n = 619) studying the effect of yoga on the severity of depression. Moderate evidence indicated a beneficial short-term effect of yoga compared to usual care, and limited evidence indicated such a benefit compared to relaxation and aerobic exercise.93 Aside from the physiological benefits of yoga, the mindfulness component may also provide a form of focus that may quell rumination (which is common in depression). At this point, distinguishing between the different types of yoga is not possible, although initial studies using Hatha and Vinyasa yoga both appeared promising.94,95 Tai Chi Tai chi combines martial arts and meditative movements that promote balance and healing of the mind and body. Tai chi involves a series of slowly performed, dancelike postures that flow into one another. As it comprises concentration, balance, muscle relaxation, and relaxed breathing, tai chi shows potential for becoming widely integrated into the prevention and rehabilitation of a number of medical and psychological conditions. One recent meta-analysis was performed on three RCTs that used depression as an outcome measure and demonstrated that tai chi interventions have beneficial effects for various populations on a range of psychological well-being measures including depression, anxiety, general stress management, and exercise self-efficacy.96 The authors concluded that despite these positive outcomes, the studies had significant methodological limitations, and more RCTs with rigorous research design are needed to establish the efficacy of tai chi in improving psychological well-being and its potential to be used in interventions for populations with various clinical conditions.

OTHER TRADITIONAL HEALING TECHNIQUES Although well-designed clinical studies investigating the role of hypnosis and imagery in the treatment of

5  Depression

depression are limited, centuries of experience in traditional healing systems (e.g., Ayurvedic, Tibetan) support this kind of therapeutic approach. In our experience, these mind–body techniques are often extremely useful therapeutic adjuncts that appear to enhance the efficacy of other treatments. Emerging data suggest that relaxation therapy appears promising.97 Some evidence has also shown the effectiveness and durability of prayer as an adjunct to other therapy for depression.98,99 We recommend that interested patients explore one of these approaches (see Chapter 94, Relaxation Techniques).

ACUPUNCTURE Acupuncture has been used for centuries in Asia for the treatment of virtually all known disease states. The exact mechanism of action is unknown, but human and animal studies have demonstrated that the stimulation of certain acupuncture points can alter neurotransmitter levels.100 The United Nations World Health Organization recognized acupuncture as effective in treating mild to moderate depression. Published data suggest that acupuncture, including manual-, electrical-, and laser-based modalities, is a generally beneficial, well-tolerated, and safe monotherapy for depression. However, acupuncture augmentation in antidepressant partial responders and nonresponders is not as well studied as monotherapy.101 A recent review of the current literature (January 2000 through April 2013) for acupuncture in cancer-related psychological symptoms showed positive results for acupuncture for the treatment of depression, anxiety, sleep disturbance, and for improving quality of life, with most results showing statistical significance. However, only a handful of acupuncture studies were specifically designed to evaluate depression, sleep disturbance, and quality of life as primary outcomes. Published studies in cancer patients and survivors show that acupuncture treatment is not only safe but also more acceptable, with fewer side effects than standard of care pharmacological treatments like antidepressants.102 However, there are several limitations of these studies (small sample sizes, imprecise enrollment criteria, problems with randomization and blinding, brief duration of study, and lack of follow-up); thus evidence supporting acupuncture for depression remains inconclusive pending further study. The Cochrane Reviews investigators concluded that evidence was insufficient to recommend acupuncture for depression.103,104

PHOTOTHERAPY Phototherapy is commonly used for patients with seasonal affective disorder and appears to be useful as an adjunctive modality with pharmacotherapy in both unipolar and bipolar depression.105 The effect of phototherapy is thought to involve manipulation of the sleep-wake cycle and biological rhythms. Two meta-analyses supported at least modest benefit of bright light phototherapy when compared with placebo for nonseasonal depression.106,107 In small studies, it appears to be an effective adjunct for adolescents, adults, and the elderly.108–110 The APA guidelines for the treatment

41

of major depressive disorder consider bright light therapy a low-risk and low-cost option.111 Consider recommending 30 to 60 minutes of bright, white light (full-spectrum, 10,000 Lux) daily from special bulbs, lamps, or light boxes.

PHARMACEUTICALS Antidepressants are believed to work by inhibiting the degradation and reuptake of neurotransmitters important in regulating psychological and neurovegetative function (serotonin, norepinephrine, dopamine), thus increasing neurotransmitter availability at the synaptic level. Newer theories suggest that pharmaceuticals may also mediate intracellular signaling systems that affect neurotrophic factors vital to the functioning of neuronal systems involved in mood regulation. Attempts to determine the most cost-effective approach to treating depression are limited by the quality of these evaluations, but SSRIs and newer antidepressants such as venlafaxine, mirtazapine, and nefazodone consistently are superior to tricyclic antidepressants (TCAs).112 Systematic reviews suggest that escitalopram and sertraline may offer the best combination of efficacy and tolerability.113,114 Studies of antidepressant medications increasingly are questioned because of the potential bias owing to unblinding, given that side effects of the drugs (as opposed to inert placebos) may reveal the identity of the true medication to participants or investigators. Trials using an “active” placebo that mimics some of the side effects of antidepressants to counteract this potential bias suggest that differences between antidepressants and active placebos are small.115

Selective Serotonin Reuptake Inhibitors and Mixed Reuptake Blockers The APA continues to recommend the use of an SSRI as first-line treatment for all levels of depression: mild, moderate, and severe.116 Recommendations for secondary steps include switching or augmenting current therapy (pharmacotherapy or psychotherapy) and depend on the initial treatment choice. Maintenance therapy is defined as continuation of the initial treatment to prevent recurrence of depression. For acute treatment of major depressive disorder (MDD), approximately 60% of patients respond to second-generation antidepressants117 with a 40% relapse rate after 1 year.118 A relatively recent meta-analysis of second-generation antidepressants summarized 4 comparative trials and 23 placebo-controlled trials and found that second-generation antidepressants were generally comparable to each other.119 Safety in overdose and side effect profiles for SSRIs and mixed reuptake blockers are greatly improved over those of cyclic antidepressants and monoamine oxidase inhibitors. Even so, one-half of all patients discontinue their medication in the first 4 months after treatment initiation, and two-thirds of these patients report a side effect as the reason for stopping treatment.120 In addition, meta-analyses of antidepressant medications have reported only modest benefits over placebo treatments.121 Be aware that concern is emerging over the longterm effects of SSRIs, including uncommon but serious

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PART II  Integrative Approach to Disease

neurologic sequelae of seizures and extrapyramidal symptoms,122 as well as worsening of long-term outcomes despite effective short-term control.123 The Food and Drug Administration (FDA) has mandated a black box warning on SSRIs regarding the risk of increasing suicidality in children and adolescents. This risk appears to occur within the first 2 weeks of initiating therapy, and whether this risk exists for adults is unclear.120 Some work suggests that adults treated with antidepressant drugs, including SSRIs, are no more likely to attempt or complete suicide than those not treated with an antidepressant.124

Dosage

See Table 5.1. Precautions

Nausea, cramping, agitation, insomnia, headache, decreased libido, delayed ejaculation, erectile dysfunction, and anorgasmia have been reported in patients taking SSRIs.120 Gastrointestinal side effects are more pronounced with sertraline but may be minimized by taking the drug with food and water. Fluoxetine

TABLE 5.1 Drug and Supplement Dosages Used in Depression Treatment Drug/supplement

Initial dose (mg/day†)

Range (mg/day†)

Frequency

Vitamin B complex 100

1 tablet

—

Daily

Folic acid or L-methylfolate

400 mcg

400–800 mcg

Daily

Fish oil

1000

1000–6000

Daily

SAMe (1,4-butane-disulfonate)

200

200–800

bid

Hydroxytryptophan (enteric coated)

100

100–200

tid

St. John’s wort (standardized to 5% hyperforin)*

300

900–1200

tid

Saffron

30 mg

bid

Selective Serotonin Reuptake Inhibitors and Mixed Reuptake Blockers Fluoxetine

20

20–60

Daily (am)‡

Sertraline

50

50–200

Daily

Paroxetine

20

20–60

Daily (am)

Paroxetine, extended release

12.5

25–75

Daily

Citalopram

20

20–60

Daily

Escitalopram

10

10–20

Daily

Serotonin Norepinephrine Reuptake Inhibitors Venlafaxine, immediate release

37.5

75–375

bid

Venlafaxine, extended release

37.5

75–375

Daily (at bedtime)

Desvenlafaxine

50

50

Duloxetine

60

60–120

Divided daily–bid

Dopamine Norepinephrine Reuptake Inhibitor Bupropion, immediate release

150

300–450

tid‖

Bupropion, sustained release

150

300–400

bid

Bupropion, extended release

150

300–450

Daily

Nefazodone

50

200–300

bid

Trazodone

150

150–400

bid–tid

Serotonin Modulators

Norepinephrine Serotonin Modulator, Alpha 2 Antagonist Mirtazapine

15

15–45

Daily (at bedtime)

bid, twice daily; SAMe, S-adenosylmethionine; tid, three times daily. *Cytochrome P-450 3A4 and drug pump P-glycoprotein induction by St. John’s wort requires that care be taken when prescribing this botanical in the setting of other drugs metabolized along these pathways. Perhaps the most clinically relevant interactions occur with cyclosporine (lowering serum cyclosporine concentration) and with other antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs; serotonin syndrome), antiretroviral therapy (reducing the concentration of protease inhibitors in patients infected with human immunodeficiency virus), and warfarin-type anticoagulants (increasing anticoagulation). Concern exists that St. John’s wort may interfere with the efficacy of oral contraceptives. Avoid the use of St. John’s wort concurrently with SSRIs; also avoid its use in pregnancy and lactation. High doses may predispose patients to photodermatitis. †Unless otherwise indicated. ‡Maximum range, 20 to 80 mg. §Doses greater than 100 mg should be divided dose, with the greater dose given at bedtime. ‖Initial dose: 100 mg bid for 3 days; then 100 mg tid.

5  Depression

is generally the most activating. Paroxetine has mild anticholinergic properties, including nausea and possibly weight gain. Venlafaxine has side effects similar to those of the other SSRIs but may cause serious hypertension over time. Although venlafaxine and paroxetine may have an increased risk of nausea, this can be reduced by using the extended-release forms.120 Citalopram and escitalopram have the fewest side effects and the least impact on the cytochrome P-450 enzyme system. Duloxetine appears to play a role in mediating chronic pain and appears effective in older patients.125 Rare side effects of SSRIs may include increased risk of gastrointestinal bleeding when these drugs are used with nonsteroidal antiinflammatory drugs, but more research is needed.120 Other rare side effects include cardiac conduction abnormalities with venlafaxine and liver enzyme abnormalities with duloxetine.120

Tricyclic Antidepressants TCAs have significant side effects (anticholinergic effects, weight gain, and cardiac dysrhythmias) and can be lethal in overdoses as small as an average 10-day supply.

Heterocyclic Serotonin Modulator and Dopamine Norepinephrine Reuptake Inhibitor Antidepressants Heterocyclic antidepressants are much safer than TCAs in overdose, and they have side effect profiles that make them useful in specific clinical circumstances. Several studies have demonstrated that heterocyclic antidepressants are equally effective as SSRIs.126 Amoxapine is useful in treating psychotic depression. Trazodone is highly sedating and is useful in low doses (25 to 50 mg nightly) when taken in combination with SSRIs to induce sleep. Bupropion is highly stimulating and may be a good option for patients wishing to discontinue smoking tobacco; it also has decreased fatigue and somnolence, but it is associated with seizures in underweight people. Nefazodone has anxiolytic properties and may be useful in patients who develop anxiety and insomnia while taking SSRIs. Nefazodone and bupropion also tend to have fewer sexual side effects compared with the SSRIs and serotonin norepinephrine reuptake inhibitors. Nefazodone and bupropion have the least likelihood of causing weight gain compared with SSRIs, whereas mirtazapine increases appetite and tends to cause weight gain. M ­ irtazapine also increases fatigue and somnolence, which may be desirable in some cases.120 Rare side effects that need further investigation in heterocyclic antidepressants include the following: seizures and atopic reactions with bupropion; thrombocytopenia, neutropenia, and bone marrow suppression with mirtazapine; and hepatotoxicity, cardiac conduction problems, and priapism with trazodone.

ELECTROCONVULSIVE THERAPY Electroconvulsive therapy (ECT) reportedly is effective in achieving remission in 70% to 90% of patients with

43

depression within 7 to 14 days in clinical trials (although it is less effective in community settings).127 Generally, ECT is reserved for suicidal, psychotic, or catatonic patients; it is also helpful in patients refractory to other treatment modalities. ECT should be used with caution in patients with recent myocardial infarction, cardiac arrhythmia, or intracranial space-occupying lesions. Transient postictal confusion and anterograde and retrograde memory impairment are expected.111 Dosage

ECT, which requires referral to an experienced treatment center, generally involves sessions three times a week for up to 4 weeks, until symptoms abate.

THERAPIES TO CONSIDER FOR DEPRESSION Estrogen Replacement Therapy No abnormality of ovarian hormones has been identified that distinguishes women with depression from those without depression during the menopause transition.128 However, estrogen replacement was demonstrated to reduce symptoms in perimenopausal and postmenopausal women with depression in some small studies, and discontinuation of hormone replacement therapy (HRT) appears to be associated with the rapid recurrence of depression in some women with a history of depression.129 An RCT comparing HRT (estradiol valerate 2 mg, dienogest 2 mg) with placebo suggests that in women with mild to moderate depression in the setting of postmenopausal syndrome, HRT clearly and clinically relevantly reduced symptom severity by the Hamilton Rating Scale for Depression (HAM-D) at 24 weeks.130 Studies assessing the relationship between hormone status and depression are inconsistent, and this topic remains an active area of research. Practitioners should consider recommending HRT after weighing the risks and benefits.

Transcranial Magnetic Stimulation Transcranial magnetic stimulation uses a magnetic coil close to the scalp to generate rapidly alternating magnetic fields to produce electrical stimulation of superficial cortical neurons. It requires no general anesthesia and has minimal side effects. This technique was cleared by the FDA in 2008 for use in patients with major depressive disorder who have not responded adequately to at least one antidepressant trial. Metaanalysis suggests that TMS may be as effective as electrical conductive therapy (ECT) for nonpsychotic depression.131

Aromatherapy Aromatherapy, which is the use of essential oils most often topically combined with MT or as inhaled vapors, has roots in ancient healing traditions. Several small studies demonstrate the impact of aroma on mood. One small open pilot trial found that adjunctive

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PART II  Integrative Approach to Disease

aromatherapy allowed for reductions in the dose of antidepressants compared with usual therapy. This nonrandomized trial included patients using various types and doses of antidepressants.132 Short-term but not persistent benefits were found for aromatherapy MT with citrus oil in patients with cancer who were dealing with depression.133 Aromatherapy may be promising as a gentle adjunctive therapy, but larger, well-designed trials are necessary before conclusions can be drawn.

Music Therapy In music therapy, patients actively perform or listen to music to promote health and healing. Numerous trials of music therapy, largely in an older population, suggest potential antidepressant benefits when this modality is added to usual care, and a dose effect exists with increased response as treatment continues.134–136 Most trials are small and lack blinding to intervention and appropriate control for attention of professionals. In addition, concurrent interventions that are not music specific (e.g., guided imagery and relaxation) make conclusions difficult to draw. A Cochrane Review identified only five trials meeting inclusion criteria and concluded that although music therapy is well tolerated by people with depression and appears to be associated with improvements in mood, the small number and low quality of studies preclude clear determination of effectiveness until better studies are conducted.137 Although proof of benefits will require more thorough study, music therapy may be a useful intervention, especially for the elderly, in whom avoiding polypharmacy is of great importance.

Sleep Deprivation Therapy Sleep deprivation therapy (SDT) is defined as maintaining wakefulness in patients all or part of the night. Multiple studies have suggested a rapid antidepressant effect of sleep deprivation therapy, but unfortunately,

the effect tends to be limited, often followed by full or partial relapse after recovery sleep or even small naps. Some trials have suggested a more durable effect may be achieved through the addition of phototherapy or sleepphase advancement.138 One limitation of these studies is the inability for blinding, but chronobiology remains an active area of depression research.

NOVEL TREATMENTS HAVING PRELIMINARY STUDIES Psilocybin A small pilot study investigated the effect of psilocybin on 12 patients with advanced-stage cancer and a diagnosis of adjustment disorder with anxiety and generalized anxiety disorder. Using a crossover design, the patients were treated with psilocybin and niacin placebo (to cause flushing) several weeks apart. Psilocybin did not cause any clinically significant adverse effects. It caused a significant decrease in anxiety, as assessed by the State-Trait Anxiety Inventory at 1 and 3 months after treatment, and improved mood, as measured by the Beck Depression Inventory after 6 months.139

Botox The theory that treatment of frown lines with botulinum toxin might improve the mood of depressed patients might seem farfetched. Wollmer and colleagues140 studied the effect of injecting botulinum toxin into 3 sites in the glabella region of 15 depressed patients who were stable on up to 2 antidepressant treatments. The treatment was the same as that used in the cosmetic treatment of frown lines, and 15 participants received a placebo of saline injections at the same sites. There was a significant decrease in depression scores from 2 weeks to the end of the trial at 4 months for the active treatment relative to placebo. Similar results were seen on the Beck Depression Inventory and the Clinical Global Impressions Scale.140

PREVENTION PRESCRIPTION The following steps are recommended for prevention of depressive symptoms: • Remove exacerbating factors. • Review current medications and supplements that could be contributing to depression, and consider decreasing dosages or discontinuing drugs that are suspect if they are not vital to the patient’s well-being. • Recommend a whole foods/low–processed foods diet such as the Mediterranean or antiinflammatory style eating plan, low in refined sugar (sucrose), , and alcohol. Encourage a diet rich in omega-3 fatty acids. Recommend two or three servings of cold-water fish (salmon, herring, mackerel, sardines) each week and 2 tablespoons of ground flaxseed or flaxseed oil daily. • Consider recommending vitamin D3 1000 units daily. • Consider recommending a B-complex vitamin daily. • Prescribe physical activity. Encourage daily aerobic (e.g., walking, jogging, cycling) or anaerobic (weightlifting) exercise. Explore options, and help patients select activities they feel are enjoyable. Emphasize starting slowly and setting realistic short-term goals. Gradually increase to an ideal exercise prescription (see Chapter 91, Writing an Exercise Prescription). • Foster an increase in a sense of community and investment in meaningful relationships to reduce social isolation.

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5  Depression

THERAPEUTIC REVIEW LIFESTYLE • Suggest regular practice of aerobic or anaerobic ­exercises most days of the week. • Encourage activities that will increase social ­connection and enhance meaningful relationships. NUTRITION • Eliminate simple sugars from the diet. • Consume a Mediterranean-style or whole foods (low–processed foods) diet.

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DIETARY SUPPLEMENTS AND BOTANICALS • Vitamins: Augment conventional antidepressant medication with vitamin B complex and 400 mcg to B 1 mg of additional folic acid (L-methylfolate) daily. • St. John’s wort: Take 900 mg daily in three equal doses. Choose a product standardized to a minimum of 2% to 5% hyperforin or 0.3% hypericin. Examples include Kira, or Perika. If no improvement is seen after 4 to 6 weeks, consider switching to SAMe or a pharmaceutical antidepressant. Concurrent ­psychotherapy is recommended, if this approach is A acceptable to the patient. •  S-Adenosylmethionine (SAMe): Start at 200 mg once or twice daily to minimize gastrointestinal side effects; then titrate upward to effect over 1 to 2 weeks. Initial treatment of depression may require 1600 mg daily given in two equal doses, followed by B am ­ aintenance dose of 200 mg twice daily. If recommending a pharmaceutical antidepressant, consider using SAMe initially (because of its rapid onset of action) along with it to minimize the latency period. SAMe may be withdrawn after 4 to 6 weeks. • If SAMe is given without a pharmaceutical antidepressant, consider switching to another agent if no resolution of symptoms is noted after 2 weeks. Choose a product containing 1,4-butane-­disulfonate (Actimet), which is stable for up to 2 years at room temperature. Concurrent psychotherapy is ­recommended, if this approach is acceptable to the patient. • Fish oil: Take 1 g daily. If this dose is not effective, consider titrating up to 6 g of omega-3 fatty acids. In the case of an intake higher than 3 g per day, caution must be used because antiplatelet effects

2

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are more likely. Choose a product with at least 60% EPA that also includes DHA and that has been tested for pesticides and heavy metal residues and keep B refrigerated. PSYCHOTHERAPY The combination of supportive psychotherapy with antidepressant supplements or pharmacotherapy is generally recommended. Primary care physicians can provide limited psychotherapy at frequent visits to monitor lifestyle modifications, dietary supplements, or drug therapy. Alternatively, referral for cognitive or interpersonal therapy is recommended. PHARMACEUTICALS If no improvement is obtained with the use of lifestyle modification measures and dietary supplements (or if the patient has severe depression), discontinue the supplements, and start a pharmaceutical antidepressant. All currently approved antidepressant drugs are equally effective and have similar latency periods.47 Choice of a selective serotonin reuptake inhibitor, mixed reuptake blocker, or heterocyclic antidepressant should be guided by matching the most appropriate side effect profile to each patient’s symptoms. Continue treatment for at least 6 months after improvement, and consider full-dosage maintenance if the patient has a history of recurrent depression ([moderate to severe depression] or [mild depression]). If only a partial response has occurred at 6 weeks, either change the class of antidepressant medication or continue the antidepressant and consider adding lithium carbonate, 300 mg three times a day (necessitates experience in monitoring serum levels), or liothyronine sodium (Cytomel), 25 to 50 mcg. PHOTOTHERAPY Suggest phototherapy with 30 to 60 minutes of bright, white (full-spectrum, 10,000 Lux) light daily from ­special bulbs, lamps, or light boxes.*

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REFERRAL Consider referral to a psychiatrist if the patient remains refractory to treatment, is suicidal or psychotic, or ­requires psychiatric hospitalization or electroconvulsive therapy or transcranial magnetic stimulation.

*Information and therapeutic lights are widely available, including from the following manufacturers: BioBrite, Inc., 1-800-621-LITE (1-800-621-5483), www.biobrite.com; and SunBox Company, 1-800-548-3968, www.sunboxco.com

REFERENCES

Key Web Resources American Psychiatric Association. http://www. psychiatryonline.com/ pracGuide/pracGuide Topic_7.aspx http://www.psychiatry.org/ dsm5 http://www.phqscreeners. com/overview.aspx

http://www.consumerlab.com http://naturaldatabase. therapeuticresearch.com

American Psychiatric ­Association Guidelines for Treatment of Major Depression

The PHQ-2 is a useful tool for screening. The PHQ-9 questionnaire is a useful tool to diagnose and monitor depression treatment. Independent testing of dietary supplements Evidence-based resources on dietary supplements

References are available online at ExpertConsult.com.

REFERENCES

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