Characteristics Associated With Swallowing Changes After Concurrent Chemotherapy and Radiotherapy in Patients With Head and Neck Cancer Joseph K. Salama, MD; Kerstin M. Stenson, MD; Marcy A. List, PhD; Loren K. Mell, MD; Ellen MacCracken, MS;Ezra E. Cohen, MD; Elizabeth Blair, MD; Everett E. Vokes, MD; Daniel J. Haraf, MD Objective: To define factors that acutely influenced swal- to assess
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Alternative treatments for depression: empirical support and relevance to womenAlternative Treatments for Depression:
Empirical Support and Relevance to Women
Rachel Manber, Ph.D.; John J. B. Allen, Ph.D.;
and Margaret M. Morris, Ph.D.
Copyright 2002 Physicians Postgraduate Press, Inc.
Received Aug. 7, 2001; accepted Dec. 17, 2001. From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford,Calif. (Dr. Manber); the Department of Psychology, University of Arizona,Tucson (Dr. Allen); and Sapient, San Francisco, Calif. (Dr. Morris). The preparation of the manuscript for this article was supported in part by grant MH56965 from the National Institutes of Health, Bethesda, Md.
(Drs. Manber and Allen), and by grant HS09988 from the Agency forHealthcare Research and Quality, Rockville, Md. (Drs. Manber andMorris). Presented at the Summit on Women and Depression, October 5–7, Background: This article is a critical review
of the efficacy of selected alternative treatments In the spirit of full disclosure and in compliance with all ACCME Essential Areas and Policies, the faculty for this CME activity were asked for unipolar depression including exercise, stress to complete a full disclosure statement. The information received is as management techniques, acupuncture, St. John’s follows: Drs. Manber, Allen, and Morris have no significant commercial wort, bright light, and sleep deprivation. Issues relationships to disclose relative to the presentation. related to women across the life span, including Corresponding author and reprints: Rachel Manber, Ph.D., Department pregnancy and lactation, are highlighted.
of Psychiatry and Behavioral Sciences, Stanford University, 401 QuarryRd., Suite 3301, Stanford, CA 94305 (e-mail: [email protected]). Data Sources: Evidence of efficacy is based
on randomized controlled trials. A distinction ismade between studies that address depressivesymptoms and studies that address depressive ndividuals suffering from depression, regardless of gen- disorders. The review emphasizes issues related der, often seek alternative treatments.1 The popularity to effectiveness, such as treatment availability, of these alternative treatments may reflect, in part, the limi- acceptability, safety, and cost and issues relevant tations of extant conventional treatments. The prescription Data Synthesis: Exercise, stress reduction
of antidepressant medications is the most common treat- methods, bright light exposure, and sleep depriva- ment for depression, for both women and men. Although a tion hold greater promise as adjuncts to conven- wide variety of antidepressant medications and strategies tional treatment than as monotherapies for major for the medical management of depression have been de- depression. The evidence to date is not suffi- veloped,2 antidepressant medications are not universally ciently compelling to suggest the use of St. John’swort in favor of or as an alternative to existing effective nor are they uniformly acceptable. Approximately U.S. Food and Drug Administration–regulated 30% to 35% of individuals completing research protocols compounds. Initial evidence suggests that acu- involving antidepressant medications do not respond to puncture might be an effective alternative mono- treatment, and the rates of nonresponse are even higher therapy for major depression, single episode.
(approximately 50%) for individuals with chronic depres- Conclusion: This review indicates that some
unconventional treatments hold promise as alter- sion.3,4 Many patients terminate treatment prematurely be- native or complementary treatments for unipolar cause they do not tolerate the side effects associated with depression in women and have the potential to antidepressant medications.5 Even the newer antidepressant contribute to its long-term management. Addi- medications, which have more favorable side effect pro- tional research is needed before further recom- files than the older agents, are often discontinued because mendations can be made, and there is an urgentneed to carefully document and report the fre- of unwanted treatment-emergent symptoms, such as sexual quency of minor and major side effects.
dysfunction, insomnia, weight gain, and a subjective sense (J Clin Psychiatry 2002;63:628–640) of cognitive and emotional blunting. Rates of dropouts thatare attributed to medication side effects are approximately15% in research studies.3 In addition, some patients whoare otherwise open to taking antidepressant medicationsmay not be willing to do so during specific life stages, suchas pregnancy and lactation, and other patients may have co-morbid medical conditions for which the use of antidepres-sant medications is contraindicated.
Alternative Depression Treatments: Relevance to Women Psychotherapy is another effective, well-researched, article concludes with a discussion of directions for future and widely used treatment for depression. In particular, research and methodological challenges associated with cognitive therapy and interpersonal psychotherapy have the systematic investigation of the efficacy and effective- efficacy comparable to that of antidepressant medications.5 Like antidepressant medications, psychotherapy is neitheruniversally effective nor uniformly acceptable. Although the reasons for discontinuing psychotherapy differ fromthe reasons for discontinuing antidepressant medications, rates of withdrawal from treatment are similar.3 Moreover, Despite the fact that over 1000 studies have evaluated Copyright 2002 Physicians Postgraduate Press, Inc.
empirically supported psychotherapies for depression are the impact of exercise on depressive symptoms,11 few have often not available, accessible, or affordable for many examined its efficacy in clinical samples of individuals who met DSM criteria for major depressive disorder The limitations of these established treatments suggest (MDD). Similarly, few studies have included a placebo or that those with depression would welcome alternative a no-treatment control. One of these studies focused on treatments. In fact, depression is among the most common older adults aged 50 to 77 years who met DSM-IV criteria conditions for which patients seek alternatives to conven- for MDD.12 These patients were randomly assigned to re- tional therapies.1,6 The 2 most common alternative treat- ceive a group aerobic program 3 times a week, antidepres- ments sought for a principal complaint of depression are sant medication (sertraline hydrochloride), or a combina- self-help groups and relaxation,1,6 but consumer satisfac- tion of the two. Pill placebo and no-treatment control tion is greater for self-help measures such as exercise and groups were not included. Approximately two thirds of the diet changes, as evidenced by response to a recent Con- participants were women, and the majority of the sample sumer Reports survey.7 Two epidemiologic surveys of pat- had a history of recurrent depression. Sixteen weeks of in- terns of use of alternative or complementary therapies8,9 tervention resulted in significant symptom reduction within and 1 survey of users of these therapies10 focused on men- each treatment group. Sixty percent to 69% of the partici- tal health and have utilized in-person psychiatric inter- pants no longer met DSM-IV criteria for MDD at the end views to determine psychopathology. The picture that of treatment, with no significant differences in response emerges from these studies is that individuals who report rates across the 3 interventions. Two group differences did or meet criteria for a mental disorder are more likely to use emerge: medication produced a significantly more rapid alternative therapies for any condition than healthy con- response, and exercise produced lower relapse rates 10 trols and that users of alternative therapies are somewhat months after remission.13 Continued adherence to an exer- less satisfied with the conventional mental health services cise routine on one’s own during the follow-up period was available to them than are nonusers (20.3% vs. 12.6%).8 associated with reduced probability of relapse (odds ratio At the same time, it appears that use of alternative thera- of 0.49). Exercise is reported to have efficacy comparable pies specifically to treat the mental disorder is limited. For to that of psychotherapy14 and to be superior to no treat- example, in one survey, only one third of complementary ment.15 Of particular relevance to this article are 2 con- therapy users with self-reported affective disorder actually trolled studies on the efficacy of exercise intervention for sought these therapies for their depressive illness.9 depressive symptoms in women. In one study,16 40 young The popularity of a given treatment, of course, provides women (aged 18 to 35) meeting Research Diagnostic Cri- no evidence for its efficacy. This article critically reviews teria17 for major and minor depression were randomly as- studies investigating the efficacy of selected alternative signed to 8 weeks of aerobic exercise (running), nonaerobic treatments for major depression. This is not a comprehen- exercise (weight lifting), or wait-list control. Both exercise sive review. Instead, it focuses on alternative treatments conditions resulted in statistically and clinically significant that were identified in epidemiologic studies to be com- improvement in depressive symptoms compared with the monly sought for relief of depression, such as exercise and wait-list control condition. Available naturalistic follow-up stress management techniques, and those whose efficacy data indicate that treatment gains were maintained at 1-year in the treatment of unipolar affective disorders has been follow-up,16 but no information was provided about the investigated, such as herbal medicine, acupuncture, bright potential contribution of continued exercise past the 8- light, and sleep deprivation. This article reviews the evi- week acute phase of treatment. Similarly, an earlier study dence for the efficacy and safety of these treatments and of a nonclinical sample (47 young female college students discusses issues related to effectiveness, including treat- with Beck Depression Inventory [BDI] scores of 11 or ment availability, acceptability, and cost. Issues related more) demonstrated that aerobic exercise was superior specifically to women across the life span are highlighted to both relaxation treatment and to a no-treatment control in the discussion of each treatment modality, when appli- condition.18 However, exercise does not appear to sig- cable, and the need for evaluating the safety of these treat- nificantly enhance treatment efficacy in individuals who ments during pregnancy and lactation is highlighted. The already receive psychiatric care for depression.19 A meta-analysis of 80 studies with mixed methodologi- cal qualities and varying type and duration of exercise estimated that the average effect size of exercise interven-tions when compared with no treatment is –0.53, reflect- Relaxation and meditation practices were identified by ing a substantially larger drop in depression resulting from the Eisenberg surveys1,6 as the most common alternative exercise than from no treatment.20 North and colleagues20 treatments sought by individuals with depressive symp- concluded that the exercise effect size increases with in- toms. There is evidence that relaxation reduces some creased duration of treatment and that efficacy was inde- symptoms of depression, such as anxiety, somatic symp- pendent of age or gender. A more recent meta–regression toms, and to a lesser extent depressed mood, but only a few analysis21 Copyright 2002 Physicians Postgraduate Press, Inc.
of randomized controlled trials investigating the randomized controlled studies have been conducted to effectiveness of exercise on the reduction of depressive evaluate the impact of relaxation and meditation on depres- symptoms estimated effect sizes for the comparison of ex- sive symptoms of individuals meeting criteria for MDD.
ercise with no treatment that are larger than those reportedby North and colleagues (–1.1).20 Many theories, both biologically and psychologically A recent randomized study compared 4 weeks of daily based, were proposed to explain the antidepressant effects practice of Sudarshan Kriya Yoga (45 minutes each ses- of exercise.16 These theories are beyond the scope of the sion) with electroconvulsive therapy (ECT) and with present article, but it is worth highlighting the possibility imipramine in a sample of 45 hospitalized patients who that the antidepressant effects of exercise might be modu- met DSM criteria for melancholic depression and had lated by behavioral and social activation. McNeil and col- Hamilton Rating Scale for Depression (HAM-D) scores of have directly compared an intervention consist- 17 or more.22 The adaptation of Sudarshan Kriya Yoga that ing of 6 weeks of walking exercises with an intervention was evaluated in this study consists of 3 sequential peri- consisting of social contact in 30 depressed older adults ods of rhythmic hyperventilation at different rates of (mean age = 72.5 years). This comparison yielded com- breathing that are interspersed with normal breathing, all parable reductions in depressive symptoms (as measured performed in a sitting position with eyes closed. The pro- by BDI scores) that were significantly larger than those cedure ends with a period of about 10 to 15 minutes of observed in the wait-list control.15 Social activation might a tranquil state (Yoga Nidra). This study demonstrated be particularly relevant when exercise is performed in a equivalent remission rates for yoga practice (67%) and group format or when the intervention targets older adults imipramine (73%), both of which were lower than the rate who might be more socially isolated than their younger of remission in response to ECT (93%). These results, which are consistent with those from an uncontrolledstudy of yoga in the treatment of dysthymia,23 indicate that an intense course of this type of yoga (6 days per week for Unsupervised and self-initiated exercise is inexpensive, 4 weeks) practiced in the inpatient environment might relatively safe, and readily available. The cost increases be beneficial. It is not clear how well these results would with increased involvement of professionals, such as a generalize to an outpatient population, to a less controlled trainer, and when exercise equipment is utilized. Issues of environment, or to other types of depression.
acceptability, motivation, and compliance place some limi- Some authors argue that certain forms of meditation, tation on the utility of exercise as a treatment for depres- such as mindfulness meditation, might be counterproduc- sion. In general, group exercise programs are associated tive during an acute depressive episode because depressed with lower attrition (26%)12 than individual programs patients may lack sufficient control of attention to learn (40%).15,16 Discontinuation rates in individual exercise pro- the additional attention control skills necessary for medi- grams are high even when monetary compensation for par- tation.24 Teasdale et al.25,26 suggest that mindfulness medi- ticipation is contingent on compliance.16 Reasons provided tation might, however, be useful in preventing episodes of for discontinuation of exercise treatment include dissatis- depression among those who have recovered from depres- faction with the exercise program and logistical difficulties sion by other means. These authors argue that mindful- in attending the classes, but not musculoskeletal injury.12 ness meditation can teach individuals who have recovered Although adherence rates among completers of the acute from depression skills of effective emotional processing phase of the exercise program were high (70%–90%),12 and that these skills may help prevent relapse.
rates in nonresearch settings are expected to be lower be- Support for the efficacy of relaxation methods other cause the close supervision and the frequent contact with a than meditation in the treatment of depression is relatively study coordinator tend to enhance compliance. Moreover, weak. A recent review of complementary treatments for exercise routines may be better suited to some depressed depression27 identified 3 randomized comparative studies people than others, as such routines are more acceptable to of relaxation in the treatment of moderate depression. The limited data provided initial evidence that relaxation may Alternative Depression Treatments: Relevance to Women enhance the response to pharmacotherapy and that it may vides some immediate increase in subjective sense of well- be superior to no treatment and to a tricyclic antidepres- being for patients who experience depressive symptoms.
sant. Yet, these results, which were based on small sample There is no evidence, however, that massage has long-term sizes, were not replicated, even though the studies were benefit or that it benefits patients who meet DSM-IV cri- teria for a major depressive episode.
Like other forms of relaxation, massage has been re- ported to decrease anxiety and somatic complaints.28 The effects of massage on depressive symptoms are more lim- Massage, relaxation, and meditation are relatively inex- ited. Some studies have documented reductions in self- pensive, safe, and accessible. Relaxation and meditation Copyright 2002 Physicians Postgraduate Press, Inc.
reported state level of depression immediately following a necessitate relatively little contact with a professional af- massage session, but no clinical evaluations of depression ter the skill acquisition phase. Unfortunately, the cited stud- severity have been reported. In other words, it is unknown ies do not report rates of adherence to or discontinuation whether the temporary improvement in well-being imme- from relaxation, meditation, or massage therapies for de- diately after a massage session translates into a clinically pression. A likely reason for noncompliance is relaxation- meaningful reduction in depressive symptoms. Further- induced anxiety, which occurs in close to one third of indi- more, most samples that were studied included individu- viduals suffering from general tension.36 als with depressive symptoms secondary to other psy-chiatric or medical disorders (e.g., bulimia, nicotine addiction, burn injuries) rather than individuals who metcriteria for primary major depression.28–31 There are only 3 Acupuncture derives from Chinese medicine. Although available studies in which the sample consisted of indi- depression is not a disease category per se in Chinese medi- viduals with symptoms of what appears to be primary de- cine, a highly similar condition, neurasthenia, is present in pression. The first study randomly assigned 32 dysthymic almost 50% of psychiatric outpatients in China,37 and many adolescent mothers who recently gave birth to receive of these neurasthenic patients would be diagnosed with massage or relaxation.32 Ten treatment sessions, twice each MDD according to the DSM. Chinese medicine character- week for 5 weeks, produced significantly lower depressed izes conditions in terms of energetic imbalances and views mood scores on the Profile of Mood States (POMS)33 im- major depression as the result of one or more patterns of mediately after a massage session as compared with pre- imbalance, depending on the precise constellation of symp- session depression scores. This immediate reduction of toms. The correspondence between symptoms of major depressed mood was observed both on the first day and on depression as defined by Western medicine and “patterns the last day (tenth session) of treatment with massage, but of energetic imbalance” as defined by the Chinese medi- pre-session depressive mood ratings did not decline across cine diagnostic system is complex,38 and its discussion is the 5 weeks of treatment. Participants receiving relaxation beyond the scope of this article. Traditional Chinese medi- did not report a similar immediate reduction on the POMS cine, like psychotherapy, provides a framework for under- depressed mood scale. Relaxation in this study consisted standing distinct symptom pictures and for developing of a combination of yoga and muscle relaxation, taught individualized treatments based on the nature of each and practiced in a group format.32 A similar reduction in individual’s particular symptom pattern. The Chinese med- depressed mood (measured by the POMS) from before icine practitioner therefore designs the treatment based on to after a massage session was reported for a sample of how each patient is experiencing depression and what pre- 52 hospitalized children and adolescents, half with ad- cipitating factors—physical, psychological, and social— justment disorder and half with depression.34 Again, pre- have contributed to the patient’s present condition.
session to post-session differences were not observed inthe control group, whose participants viewed relaxation videos for 30 minutes each day. The participants who re- Very few randomized studies have evaluated the effi- ceived massage in this mixed sample, unlike the ado- cacy of acupuncture in the treatment of major depression.
lescent mothers, did report a significant decline in pre- Only 1 double-blind, randomized, placebo-controlled session depressed mood across the 5 days of treatment.
study of acupuncture as monotreatment for major depres- In contrast, no reduction in pre-session depressed mood sion has been published.39 In this study, participants were across time was observed in the control group.34 A third randomly assigned to 1 of 3 conditions: a specific treat- study targeted older adults with elevated depression ment designed to treat the energetic imbalance thought to scores. Participants received daily massage for 1 month underlie the patient’s depression; a nonspecific treatment and provided daily massage to infants for 1 month, in a designed to treat a pattern of disharmony that was not counterbalanced order.35 Depressed affect was reported to related to the patient’s depression, but that was character- decrease more from providing than receiving massage.
istic of the patient; or a wait list. To blind the treatment Taken together, these data demonstrate that massage pro- provider, the specific and nonspecific treatment plans were developed by an assessing acupuncturist, who fol- finding is simply related to insufficient power awaits lowed a standardized manual, and were administered by the completion of the larger ongoing trial by these re- 1 of 4 other board-certified acupuncturists, who mini- searchers. The durability of treatment gains was assessed mized verbal exchange with the participant and refrained 6 months after the conclusion of treatment, at which time from assessing signs and symptoms common in Chinese 24% of patients who remitted with treatment had experi- medicine (pulse and tongue). Acupuncturists were told enced the redevelopment of a full depressive episode.40 that the study would evaluate different approaches to This figure is comparable to that seen with other treat- treating depression, derived from different theories, and ments.41 Although the study suggests that acupuncture that their task was to implement each treatment faithfully.
holds promise in the treatment of major depression, its Copyright 2002 Physicians Postgraduate Press, Inc.
Because of the fact that any 2 depressed individuals will generalizability is limited by its selective and small sample not have identical symptoms, and therefore not receive size that was restricted to young women.
the same acupuncture treatment, it is not immediately ob- A recent single-blind, placebo-controlled study exam- vious which treatments are specifically intended to ad- ined the efficacy of adding acupuncture to the tetracyclic dress a particular patient’s depression unless the treat- antidepressant mianserin in 70 inpatients with a major ment provider performs a comprehensive assessment of depressive episode.42 Patients received either a valid acu- a patient’s symptoms, which they were prohibited from puncture treatment for depression, a placebo acupuncture doing. The success of the strategy was assessed by mea- treatment, or simply continued medication with no addi- suring the acupuncturists’ ratings (following the first tional acupuncture. The specific treatment was adminis- treatment session) of their expectation regarding the ef- tered at a predefined fixed set of points that were not tai- ficacy of the treatment they provided, and the reported lored for each patient’s presentation of depression. The ratings were virtually identical for specific and non- placebo acupuncture was provided at points adjacent to the valid points of the specific treatment (i.e., at “sham” The success of this blinding strategy can be explained points). Although patients were blind to treatment condi- by an analogy between the process by which traditional tion, treating acupuncturists were not blinded. All patients Chinese medicine arrives at its prescription of points for receiving the combination of mianserin and acupuncture complex syndromes such as depression and the math- (valid or placebo) improved slightly more on measures ematical concept of a “1-way function.” A 1-way function of overall function and symptomatology (Global Assess- is a mathematical function that is significantly easier to ment Scale and Clinical Global Impressions scale) than compute in one direction (the forward direction) than in patients treated with medication alone, but no significant the opposite direction (the inverse direction). It might be differences emerged between the valid and placebo acu- possible, for example, to compute the function in the for- puncture.42 This study suggests that augmenting tradi- ward direction in seconds, but to compute its inverse could tional pharmacologic treatments with acupuncture may be take months or years, if it were at all possible. One-way somewhat helpful in improving overall function, but that functions are the basis for many encryption schemes. Like such benefit cannot be ascribed to the effect of needling at a 1-way function, traditional Chinese medicine provides specific points. On the other hand, acupuncture treatments clear rules to map the set of depression symptoms and provided in this study were not optimally effective from their associated patterns of “energetic imbalance” to a set the perspective of Chinese medicine because they were of acupuncture points. At the same time, deciphering from not specifically tailored to each patient’s symptom pic- a given set of points precisely what it was mapped from ture. Additionally, this study did not evaluate how the (i.e., what specific constellation of symptoms it is treat- addition of acupuncture impacted traditional measures of ing) is much more difficult because the number of possible depressive symptomatology such as the HAM-D or other combinations is very large and not unique to depression.
symptoms that are part of the DSM criteria for MDD.
Participants in this double-blind study were 38 women Several studies conducted in China and the former between the ages of 18 and 45 who met DSM-IV diagnos- Soviet Union evaluated acupuncture as a treatment for tic criteria for current MDD, nonchronic, without psy- depression and other psychiatric conditions. Polyakov43 chotic features and who did not meet criteria for any other reported that acupuncture reduced the principal symptoms Axis I disorder. Specific acupuncture treatment produced of depression and lessened the severity and prominence a significant reduction in symptoms at the end of treat- of supplementary symptoms in an open-label treatment ment, and the reduction of symptom severity, indepen- of 167 depressed patients. Two other case-report studies dently assessed by a clinical interview and by self-rating, found significant improvement of symptoms in patients was significantly greater for the specific group than for diagnosed with neurasthenia44 and other psychiatric pre- the nonspecific group. The reduction of depression scores sentations involving depressed mood.45 Two Chinese stud- observed in the specific group, however, was not signifi- ies focused on electroacupuncture in the treatment of cantly larger than that in the no-treatment control group major depression and found that it produced decreases in this small sample. The determination of whether this in HAM-D scores comparable to treatment with amitrip- Alternative Depression Treatments: Relevance to Women tyline.46,47 Point selection and method of needling varied across these studies. Some included no stimulation, oth-ers included manual stimulation, and yet others included By far the most commonly used, and most widely stud- electrostimulation. Although far from definitive, taken ied, herbal compound for depression derives from the together, these studies suggest that it might be possible plant Hypericum perforatum, more popularly known as to obtain favorable results using acupuncture to treat St. John’s wort. Hypericum is widely used in Europe, par- mood-related symptoms, including depression, but this ticularly in Germany, where it is the most common antide- hypothesis needs to be directly tested in well-designed pressant treatment.51 Its use in North America has recently St. John’s wort contains a variety of compounds, and Copyright 2002 Physicians Postgraduate Press, Inc.
there is controversy over which of the many compounds Acupuncture appears to be well tolerated as evidenced provide therapeutic effects. Many studies have used a stan- by the low dropout rate (13%) reported by Allen and col- dardized extract of hypericin. Although it was initially leagues.39 This rate compares favorably with the rates thought that the hypericins were inhibitors of monoamine reported in studies of antidepressant medications or psy- oxidase (MAO), recent studies challenge this assump- chotherapy, which are 25% or more.3,5 Moreover, the ad- tion.52,53 Recent work also suggested that the therapeutic dition of electroacupuncture to imipramine resulted in effect may be derived from other compounds within St.
John’s wort, most notably hyperforin, which enhances the Acupuncture is widely available in the United States, synaptic availability of serotonin, as well as dopamine and with over 7000 acupuncturists certified by the National norepinephrine.54 It is possible that no single compound in isolation, but rather the combination of these and other Medicine (NCCAOM, http://www.nccaom.org/) and ap- compounds within St. John’s wort, is responsible for its proximately 5000 acupuncturists licensed by the Califor- nia State Oriental Medical Association (many of which arenot licensed additionally by the NCCAOM). Although the cost of acupuncture is lower than that of psychotherapy A meta-analysis of the efficacy of St. John’s wort and antidepressant medication, relatively few insurance for depression55 found that across studies judged to be companies outside the state of California provide cover- methodologically acceptable, almost all of which were conducted in Germany, St. John’s wort was superior to pla- The risks associated with acupuncture in standard prac- cebo controls and comparable to standard tricyclic anti- tice are minimal. Recent data from a total of 30,338 needle depressants. A more recent and selective review, which in- insertions (1441 sessions provided to 391 patients) indi- cluded several large and methodologically sound trials not cate that standard acupuncture, as practiced in the com- included in the cited meta-analysis, essentially corrobo- munity, is associated with some mild adverse reactions and rates these findings.56 Although the results of the recent that these adverse side effects are transient.48 The inci- meta-analysis suggest the promise of St. John’s wort, the dence of recorded systemic reactions in individual patients authors note several limitations. The studies included a was as follows: tiredness (8.2%), drowsiness (2.8%), ag- wide range of patients, measures, and interventions, includ- gravation of preexisting symptoms (2.8%), itching in the ing some that used St. John’s wort in combination with punctured regions (1.0%), dizziness or vertigo (0.8%), other preparations. The criteria for classifying patients as feeling of faintness or nausea during treatment (0.8%), depressed were not uniform and sometimes only vaguely headache (0.5%), and chest pain (0.3%). The incidence of presented. Outcome measures have seldom involved stan- recorded local reactions, expressed as a percentage of dardized clinical interviews. Daily doses of total hypericin needle insertions, was as follows: minor bleeding on with- varied widely across trials, as did the presence or absence drawal of the needle (2.6%), pain on insertion of the of substances other than hypericin that are part of St. John’s needle (0.7%), petechia or ecchymosis (0.3%), pain or wort. In addition to the concerns noted by the authors, it is ache in the punctured region after the treatment (0.1%), worth commenting that some unblinding of raters might subcutaneous hematoma (0.1%), and pain or discomfort have occurred in studies comparing St. John’s wort with in the punctured region during the needle retention traditional tricyclic antidepressants because of the differ- (0.03%). Severe adverse events such as pneumothorax, ential side effect profiles of these interventions.
cardiac injury, infection, or spinal lesions are rare when Not included in the meta-analysis or in the review the practitioner is adequately trained and have been clas- of the literature55,56 were 2 large-scale multisite, double- sified as provider’s negligence.49 A review of the literature blind, randomized controlled trials of St. John’s wort that indicates that when hygienic standards are high and acu- have since been completed57,58 and several smaller trials puncturists are well educated, the risk of adverse events reviewed by Maidment.59 The first large-scale study57 was a 3-arm study that involved randomly assigning 263 patients to receive either 1050 mg of Hypericum extract, ment of depression. Specifically, research should ask 100 mg of imipramine, or placebo. Hypericum extract was (1) Does St. John’s wort have efficacy relative to placebo found to be superior to placebo after 4, 6, and 8 weeks of across a sufficient number of studies to warrant further treatment, producing a larger reduction of depressive investigation? (2) Is St. John’s wort as effective as tradi- symptoms as assessed by the HAM-D and the Zung Self- tional antidepressants? (3) Is St. John’s wort effective for Rating Depression Scale, and greater reductions in anxi- a subset of depressed persons? (4) Is it effective and safe ety as assessed by the Hamilton Rating Scale for Anxiety.
in the longer-term treatment of depression? (5) How do On all of these measures, Hypericum extract was statisti- different dosages and extracts compare?61 and (6) What is cally indistinguishable from imipramine. Several other the interaction between St. John’s wort and prescription Copyright 2002 Physicians Postgraduate Press, Inc.
smaller trials published since the 1996 meta-analysis (re- antidepressant medication and other medications? viewed by Maidment59) reached a similar conclusion. Be-cause this trial compared a relatively high dose of Hyperi- cum extract with a relatively low dose of imipramine Although St. John’s wort has become widely available (selected to be a therapeutic dose that would minimize the in North America, the content of products labeled to con- side effect profile), it is unclear to what extent Hypericum tain St. John’s wort varies widely. Extracts from St. John’s extract would be comparable to typically employed doses wort contain at least 10 compounds that may contribute to of traditional tricyclic antidepressants. By contrast, the its pharmacologic effects,62 only 1 of which is hypericin.
second large-scale multisite, double-blind, randomized Most products available on retail shelves—as well as controlled trial, which involved 200 patients randomly as- those used in clinical trials—are standardized on hyperi- signed to 900 to 1200 mg/day of St. John’s wort extract or cin content, but vary with respect to the other compounds.
to matched placebo pills, found no differences between Additionally, because there is no independent agency cur- the 2 groups at any point across the 8-week intervention.59 rently overseeing the purity and potency of herbal prod- The study included subjects with some comorbid condi- ucts sold in North America, 2 products purporting to have tions and subjects with chronic depression and produced similar concentrations of hypericin may in fact have dif- a low rate of response, with 26.5% of those treated with ferent concentrations of hypericin and will almost surely St. John’s wort and 18.6% of those given placebo demon- have different concentrations of other compounds. Simi- strating at least a 50% reduction in HAM-D score. Similar larly labeled products therefore cannot be assumed to figures were reported for rates of remission (i.e., HAM-D have equal pharmacologic or therapeutic effects. Caveat score 7 or less at the end of treatment), although in this instance, the proportion of participants treated with St.
In terms of cost, St. John’s wort is substantially less John’s wort extract who achieved remission was signifi- expensive than traditional antidepressant medication.
cantly higher (14.3%) than for those given placebo Based on prices found at a large national drug store chain, (4.9%). Consistent with these overall negative results, a a daily dose of 900 mg of St. John’s wort extract (stan- recent Consumer Reports survey7 found that most respon- dardized to 0.3% hypericin) is about half the cost of a dents who had tried St. John’s wort thought that it helped 100-mg daily dose of imipramine and about one tenth the little, if at all. This low self-reported effectiveness might cost of a 20-mg daily dose of Prozac (fluoxetine). A com- in part be related to the heterogeneity in compounds and prehensive and systematic evaluation of side effects of potency of over-the-counter preparations of St. John’s St. John’s wort is required and has yet to be conducted.
wort and to self-medicating without a systematic and/or St. John’s wort has been used safely for large numbers of people in Germany, and the published clinical trials A third large-scale multisite study, funded by the Na- have uncovered no serious dangers from St. John’s wort tional Institutes of Health Center for Complementary and per se. In particular, there appear to be no significant ad- Alternative Medicine, is due to be completed in 2002.
verse effects on cardiac conduction.63 Side effects of St.
This trial benefits from its design, which not only involves John’s wort may include photodermatitis, gastrointestinal random assignment to St. John’s wort or placebo, but also tract upset, dizziness, dry mouth, sedation, restlessness, to the selective serotonin reuptake inhibitor (SSRI) sertra- constipation, and headache,59,62 but the number of pre- line. There is only 1 published study addressing the com- mature treatment terminations because of adverse side parative efficacy of St. John’s wort to an SSRI. In this effects is lower than for tricyclic antidepressants.55 Only 1 study of 149 elderly patients, a daily dose of 800 mg of study compared the side effect profiles of St. John’s wort St. John’s wort extract was comparable to a relatively low and an SSRI.60 It found that the frequency of adverse side dose (20 mg) of the SSRI fluoxetine in reducing de- effects was comparable for the 2 treatment groups.
pressive symptoms across 6 weeks as assessed by the There have been case reports, however, of adverse ef- fects of St. John’s wort when used in conjunction with Clearly, further research is required to determine other medications. As a result, the National Institute of whether St. John’s wort may prove effective in the treat- Mental Health has recently issued a public alert for people Alternative Depression Treatments: Relevance to Women to avoid taking St. John’s wort if they are taking indinavir difference between the 2 treatments.74 In contrast, another (a protease inhibitor used to treat human immunode- study found that participants exposed to bright light had a ficiency virus), cyclosporine (used to reduce the risk of significantly greater improvement in a global depressive organ transplant rejection), or the cardiac-related medi- score than those exposed to dim light.75 A literature-based cations digoxin and warfarin. Additionally, combining St.
comparison between the effects of bright light exposure John’s wort with an SSRI could possibly result in seroto- and pharmacotherapy concluded that light therapy pro- nin syndrome, as was recently observed in 5 elderly pa- duces faster antidepressant benefits than psychopharma- tients.64 St. John’s wort has also been reported to lead to cologic treatment76 but, to date, there have been no direct decreased bioavailability of some drugs (e.g., digoxin, randomized comparisons between bright light and medi- Copyright 2002 Physicians Postgraduate Press, Inc.
theophylline, cyclosporine, and phenprocoumon)65 and in- cations for nonseasonal unipolar depression. There are creased metabolism of other drugs, including cyclosporine, also no data on the efficacy of bright light treatment indinavir, and, relevant to many women, oral contracep- beyond 1 or 2 weeks, nor are there data concerning the tives.66 When St. John’s wort was thought to be an MAO degree to which the limited benefits of brief light therapy inhibitor, some practitioners advised people to avoid food are maintained over time. In the absence of data on these and beverages high in tyramine (since the interaction of important issues, the clinical utility of bright light expo- MAO inhibitors and tyramine can cause a rapid and un- sure in the treatment of unipolar nonseasonal depression controlled episode of hypertension). The more recent find- remains limited. Initial evidence suggests that augmenting ings that St. John’s wort is not a potent MAO inhibitor, and standard treatment for nonseasonal depression with bright the fact that many people in Germany have tolerated St.
light exposure during the winter may be beneficial,77 but John’s wort without dietary restriction, suggest that dietary this possibility needs further empirical investigation.
restriction is not a necessary precaution when taking St.
Light exposure might also be useful in the maintenance John’s wort. On the other hand, there would be no harm in of gains following standard treatment for depression, but reducing intake of tyramine-laden foods until the contro- this possibility too awaits further research. There are some versy around MAO and St. John’s wort is resolved.51 It is indications, based on small sample sizes, that bright light also worth cautioning against combining traditional anti- might be effective for the treatment of premenstrual dys- depressants with St. John’s wort. Finally, pregnant and lac- phoric disorder and postpartum depression.78–80 tating women are generally advised not to take St. John’swort even though no direct evaluations of the safety of St. John’s wort during pregnancy and lactation have been Light therapy, although generally safe, is not tolerated by all individuals. Side effects of light therapy includehypomania, present even in nonseasonal unipolar dis- order,75 jumpiness/jitteriness that is more pronouncedwith morning light exposure, headache, and nausea.81 Pre- valence rates of these side effects are estimated to range There is a large body of literature demonstrating the ef- between 8% and 16% following treatment with 10,000 ficacy of light therapy as a treatment of seasonal affective lux.81 Bright light therapy might be less acceptable than disorder.68,69 One study further demonstrated that the ob- antidepressant medication as evidenced by larger dropout served therapeutic effects of bright light exposure cannot rates.71 The cost of treatment involves the cost of a light be attributed solely to expectation.70 Efficacy appears to box ($200–$400) and the cost of consultation with a quali- be comparable to that of the antidepressant fluoxetine.71 fied health professional with knowledge and experience Although treatments vary across studies in terms of the in delivering this intervention. At present, relatively few timing of the light exposure (evening versus morning), health care providers are sufficiently trained to provide the duration of each exposure, and the duration of treat- ment, it appears that 1.5 to 2 hours of treatment daily over4 to 5 weeks produces good therapeutic results, with slight, but not robust, superiority for morning light expo-sure relative to evening exposure.70,71 While effective for the treatment of seasonal affective A large and consistent body of literature documents the disorder, phototherapy is significantly less effective for rapid and profound positive effects that a single night of the treatment of nonseasonal MDD.72,73 One controlled total sleep deprivation has on depressed mood. Peak ben- study compared the effects of bright light and dim light efits are usually observed in the afternoon following the exposures in patients with unipolar nonseasonal depres- night of sleep deprivation. This positive impact of sleep sion and found slight reduction in depression scores with deprivation on depression is opposite to its effects on 1 week of exposure to both the active treatment, bright healthy nondepressed individuals. The improvement in light, and to the placebo, dim light, with no significant mood is observed in 60% of all patients with affective disorders,82 with higher rates among patients with melan- medicine textbooks as forbidden during pregnancy as cholic unipolar depression83; those with diurnal mood vari- well as points that are identified as requiring extra caution ability, particularly those whose mood is worse in the morning82; and those with a single episode of depression.84The clinical utility of sleep deprivation, however, is quite limited, because the improvement is transient and usuallydissipates after a night of recovery sleep. Prolonged sleep This review clearly indicates that some unconventional deprivation is not only impractical but also leads to wors- treatments hold promise as alternative or complementary ening of mood.85 There are some indications, however, that treatments for unipolar depression and have the potential Copyright 2002 Physicians Postgraduate Press, Inc.
even a single night of sleep deprivation may speed thera- to contribute to its long-term management.
peutic response among those treated with antidepressant Exercise and stress reduction methods hold greater medications86 and that bright light exposure can prolong promise as adjuncts to conventional treatment than as the therapeutic effects of sleep deprivation.87,88 monotherapies for major depression. There is evidencethat exercise improves mood, but observed effect sizes in studies of its efficacy as a treatment for major depression Sleep deprivation is not well tolerated, and dropout are smaller than those observed for antidepressant medi- rates from protocols that require multiple nights of sleep cations or for psychotherapy. Moreover, issues of moti- deprivation are high.89 Worsening of symptoms is reported vation, adherence, and persistence may limit the role of in depressed individuals with psychotic features84 and in exercise in the treatment of major depression in the com- bipolar depression.90 Should future research support the munity. Future research should, therefore, focus on these utility of sleep deprivation in speeding the response to practical limitations, and ways to increase motivation and antidepressant medication and in the treatment of indi- commitment, such as the integration of psychotherapy and viduals with treatment-resistant depression, sleep depriva- tion might become an inexpensive and easily accessible Stress reduction methods, with the possible exception complementary treatment for nonpsychotic unipolar de- of Sudarshan Kriya Yoga, are not effective for treating ma- pression. Initial evidence suggests that partial sleep dep- jor depression. Nevertheless, stress reduction methods rivation might benefit women whose depression began may be useful adjuncts to empirically supported treat- during pregnancy or during the year after delivery.91 ments for depression because they can effectively reducethe anxiety that is often an associated symptom of depres- sion. Research needs, therefore, to focus on exploring what the role of stress reduction methods in the manage-ment of depression should be. For example, stress reduc- During pregnancy and lactation, depressed women are tion methods could be useful along with conventional often reluctant to take antidepressant medications. It is treatments during the acute phase of treatment, or when generally agreed that drugs, including antidepressants, added later to treat residual anxiety symptoms following should be taken during pregnancy only when obtaining no an adequate trial with a conventional method. Stress re- treatment poses a greater risk to the mother and the fetus duction therapies might also play a role in prevention of than taking the drug.92 When untreated, depression during major depression in individuals who are at risk, such as pregnancy has significant deleterious effects, including those with personal or familial history of the disorder.
low infant birth weight, preterm delivery, small infant size There is initial evidence from 1 double-blind con- relative to gestational age, infants that are difficult to con- trolled study that acupuncture might be an effective alter- sole,93–96 and postpartum depression.97 It is therefore im- native monotherapy for major depression. If this finding portant to identify safe and effective treatments for de- is replicated and if acupuncture is further shown to remain pression during pregnancy. With the exception of partial safe and effective during pregnancy and lactation, acu- sleep deprivation,91 there has been no systematic evalua- puncture could become the treatment of choice during tion of the safety of the alternative treatments discussed these sensitive periods. In addition to continued testing here during pregnancy. Absence of safety data is particu- of the efficacy of acupuncture relative to control, future larly alarming for herbs, given the common tendency to research will need to compare the efficacy of acupuncture equate “natural” with “safe.” There is an ongoing study with that of conventional treatments and investigate how (sponsored by the Agency for Healthcare Research and the treatment protocols used in clinical trials might best Quality) testing the efficacy and evaluating the safety of be disseminated to treatment providers in the community.
acupuncture as a treatment for depression during preg- Empirical support for St. John’s wort as a monotherapy nancy. The acupuncture protocol of this ongoing study for major depression is mixed. Differences between stud- has been modified so that it does not permit the use of ies may be attributed to differences in sample characteris- acupuncture points that have been classified in Chinese tics, such as disease severity, chronicity of the depressive Alternative Depression Treatments: Relevance to Women illness, and the presence of comorbid conditions. The evi- the optimal strategy for relapse prevention? What is the dence to date is not sufficiently compelling to suggest the impact of adding an alternative treatment to an existing use of St. John’s wort in favor of or as an alternative to conventional therapy, either concurrently or sequentially? existing U.S. Food and Drug Administration–regulated (For example, what combinations of conventional and compounds. Further tests of the efficacy of St. John’s wort unconventional treatments improve outcome? Do some in general and potential differential efficacy in specific combinations actually decrease efficacy of either single subgroups of patients are necessary. Future research will modality? What combinations are safe?) What aspects also need to focus on determination of what constituents of outcome are impacted by specific combinations of con- of St. John’s wort are responsible for any potential thera- ventional and unconventional therapies? (Possible aspects peutic ef Copyright 2002 Physicians Postgraduate Press, Inc.
fect. There is a need for continued evaluation to consider include rates of response, magnitude of re- of the safety of St. John’s wort in general and during preg- sponse, course to response, adherence, side effect profile, nancy and lactation, and for ways to bridge the gap be- and rates of relapse and recurrence.) Can unconventional tween the results of the clinical trials and the instantiation therapies, such as relaxation, meditation, or acupuncture, of St. John’s wort as a treatment for general use.
be used in individuals with incomplete remission follow- Neither bright light exposure nor sleep deprivation is likely to become a useful alternative monotherapy for ma- A third set of questions relates to effectiveness. Will jor depression: bright light therapy is ineffective for non- positive results from efficacy studies generalize to com- seasonal depression, and the benefits of sleep deprivation munity settings? For example, is it possible to motivate are transient. Nevertheless, these unconventional treat- depressed patients to consistently engage in an exercise ments could play a role in speeding response to pharma- program outside the context of a research protocol? Can , and they might be useful as adjunctive compo- acupuncture methods that were standardized and empiri- nents in the management of treatment-resistant depression.
cally validated be effectively disseminated and adheredto outside the controlled research environment? Should St. John’s wort be regulated? How can the combination of Evaluation of safety is of particular relevance to alter- conventional and unconventional treatments be provided native therapies because there is a prevailing miscon- ception that just because something is “natural” or “usedfor centuries,” it is safe. Adhering to the “first do no harm” principle dictates that all research on alternative treatments There is a rich literature on methodological issues faced for depression carefully document and report the fre- by treatment outcome research in general and for depres- quency of minor and major side effects. Effects reported sion in particular. This literature highlights the importance should also include secondary side effects, such as involve- of periodic assessment with standardized outcomes that ment in an automobile accident secondary to severe sleepi- include both self-report measures and structured clinical ness that could have resulted from sleep deprivation, or interviews and the importance of assessing not only change losing one’s job after an injury sustained during exercise.
in depression severity but also response, relapse, and re-currence. Many other general methodological issues that are relevant to the study of the efficacy and effectiveness It is clear from this review that many questions need to of any treatment for depression, including alternative treat- be answered before the promise of alternative treatments ments, will not be expanded here. Instead we will focus can be actualized or dismissed. These questions can be on 1 central issue: identifying adequate control groups for categorized into 3 sets. The first set is related to establish- the target treatment. The choice of control can be guided ing efficacy and safety in a clinical sample of patients by answering the following 2 important questions: (1) Is with major depression. Does a given alternative treatment the target treatment more effective than an inert treatment provide significant benefits beyond those offered by pla- or no treatment? and (2) Are specific factors contributing cebo and nonspecific therapeutic factors? Are these ben- to its efficacy above and beyond the nonspecific factors? efits comparable to those obtained by conventional treat- A wait-list (delayed treatment) group provides control ments? How long are the benefits retained? Benefits for spontaneous remission and for the potential therapeu- should be assessed both in terms of clinical significance tic effects of the attention provided to patients by the re- (percentage of patients with meaningful response) and in search process itself. Wait-list has been commonly used as terms of statistical significance (change on a continuous control in psychotherapy outcome research and can be eas- ily implemented in testing efficacy of alternative treatments A second set of questions is related to optimizing treat- for depression. Choosing an inert (vis à vis depression) ment. What is the optimal frequency and duration of treat- treatment is a challenging task that has eluded psycho- ment necessary for therapeutic response? How should therapy outcome research and has just begun to be ad- treatment gains be consolidated and maintained? What is dressed in research on the efficacy of alternative treatments for depression. Ideally, an inert treatment should share Drug names: amitriptyline (Elavil and others), cyclosporine some nonspecific factors with the target treatment (e.g., (Sandimmune and others), digoxin (Lanoxin and others), fluoxetine(Prozac and others), indinavir (Crixivan), sertraline (Zoloft), warfarin amount of and nature of interaction with the treatment pro- vider) and should not produce significantly better outcomethan either a standard placebo treatment for depression or Disclosure of off-label usage: The authors have determined that, to the no treatment. Because nonspecific factors—such as expec- best of their knowledge, no investigational information about pharma-ceutical agents has been presented in this article that is outside U.S.
tations of benefit, activation, and interaction with a caring Food and Drug Administration–approved labeling.
provider—play such an important role in the treatment ofdepression, it is difficult to find a control treatment that Copyright 2002 Physicians Postgraduate Press, Inc.
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Boletín ASOCIACION ESPAÑOLA DE ANIRIDIA ULTIMOS TRATAMIENTOS EN PACIENTES CON ANIRIDIA Dr. Juan Álvarez de Toledo Aniridia. Alternativas quirúrgicas. un tejido que no es transparente,pues contiene venas, y va a opa-cificarla. Expuso que este problema sepuede afrontar quirúrgicamente. Simposium Internacional.1 Líneas de investigación.7 Actividades de la asocia