Massage therapy decreases cancer-related fatigue: Results from a randomized early phase trial.

BACKGROUND: Cancer-related fatigue (CRF) is a prevalent and debilitating symptom experienced by cancer survivors, yet treatment options for CRF are limited. In this study, we evaluated the efficacy of weekly Swedish massage therapy (SMT) versus an active control condition (light touch [LT]) and waitlist control (WLC) on persistent CRF in breast cancer survivors. METHODS: This early phase, randomized, single-masked, 6-week investigation of SMT, LT, and WLC enrolled 66 female stage 0-III breast cancer survivors (age range, 32-72 years) who had received surgery plus radiation and/or chemotherapy/chemoprevention with CRF (Brief Fatigue Inventory > 25). The primary outcome was the Multidimensional Fatigue Inventory (MFI), with the National Institutes of Health PROMIS Fatigue scale secondary. RESULTS: Mean baseline MFI scores for 57 evaluable subjects were 62.95 for SMT, 55.00 for LT, and 60.41 for WLC. SMT resulted in a mean (standard deviation) 6-week reduction in MFI total scores of -16.50 (6.37) (n = 20) versus -8.06 (6.50) for LT (n = 20) and an increase of 5.88 (6.48) points for WLC (n = 17) (treatment-by-time P < .0001). The mean baseline PROMIS Fatigue scores were SMT, 22.25; LT, 22.05; and WLC, 23.24. The mean (standard deviation) reduction in PROMIS Fatigue scores was -5.49 (2.53) points for SMT versus -3.24 (2.57) points for LT and -0.06 (1.88) points for WLC (treatment-by-time P = .0008). Higher credibility, expectancy, and preference for SMT than for LT did not account for these results. CONCLUSION: SMT produced clinically significant relief of CRF. This finding suggests that 6 weeks of a safe, widely accepted manual intervention causes a significant reduction in fatigue, a debilitating sequela for cancer survivors. Cancer 2018;124:546-54. © 2017 American Cancer Society.

A preliminary descriptive report of the longevity of the effects of Swedish Massage therapy for subjects with Generalized Anxiety Disorder.

OBJECTIVE: Generalized Anxiety Disorder (GAD) is a prevalent and costly disorder, and many patients may prefer non-traditional treatment. A proof-of-concept study demonstrated the efficacy of Swedish Massage Therapy (SMT) as a monotherapy for treatment of GAD. Subjects were followed-up 6-12 months after study completion to evaluate post-treatment outcome. METHODS: Subjects were enrolled into a randomized, single-masked clinical trial between March of 2012 and May of 2013. Forty-seven untreated subjects with DSM-IV diagnosis of GAD were randomly assigned to 6 weeks of twice-a-week light touch (LT) followed by 6 weeks of twice-a-week SMT, or 12 weeks of twice-a-week SMT. The primary outcome measure was reduction in Hamilton Anxiety Rating Scale (HAM-A) scores after six weeks of SMT versus LT. Qualifying participants received a follow-up survey to investigate whether the benefits of SMT for GAD were sustained. RESULTS: 28 of 40 subjects completed at least 12 sessions of SMT and were sent the follow-up survey. Of the 19 subjects with follow-up, nine (47%) reported no return of GAD symptoms up to 1 year after study completion. There were no differences between those randomized to 12 weeks SMT and those receiving 6 weeks LT followed by 6 weeks SMT. Of those reporting a return of some symptoms, 50% associated symptom return with a stressful life event. INTERPRETATION: In this first monotherapy trial of SMT for the treatment of GAD, follow-up results suggest that the beneficial effects of SMT may last up to 1 year after end of treatment.

Individuals with depression exhibiting a pro-inflammatory phenotype receiving omega-3 polyunsaturated fatty acids experience improved motivation-related cognitive function: Preliminary results from a randomized controlled trial.

Cognitive impairment related to major depressive disorder (MDD) is highly prevalent, debilitating and is lacking in effective treatments; dysregulated inflammatory physiology is a putative mechanism and may represent a therapeutic target. In depressed individuals exhibiting a pro-inflammatory phenotype who were enrolled in a 12-week randomized placebo-controlled trial of 3 doses of omega-3 polyunsaturated fatty acids (ω-3-FA), we examined: (i) the relationship between dysregulated inflammatory physiology and baseline cognitive impairment; (ii) improvement in cognitive impairment following treatment; and (iii) the association between baseline inflammatory biomarkers and change in cognitive impairment for those receiving treatment. We randomized 61 unmedicated adults aged 45.50 years (75% female) with DSM-5 MDD, body mass index >25 kg/m2, and C-reactive protein (CRP) ≥3.0 mg/L to three doses of ω-3-FA (1, 2, or 4 g daily) or matching placebo. Analyses focused on 45 study completers who had inflammatory biomarkers assessed [circulating CRP, interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) as well as lipopolysaccharide (LPS)-stimulated concentrations of IL-6 and TNFα in peripheral blood mononuclear cells (PBMC)] and on the highest dose ω-3-FA (4 g daily; n = 11) compared to placebo (n = 10). Impairment in motivational symptoms (e.g., alertness, energy, enthusiasm) and higher-order cognitive functions (e.g., word-finding, memory) were assessed by a validated self-report measure. Among all 45 participants at baseline, lower concentrations of IL-6 in LPS-stimulated PBMC were associated with greater impairment in higher-order cognitive functions (r = -0.35, p = .02). Based on hierarchical linear modeling, individuals receiving 4 g/day of ω-3-FA reported significant improvement in motivational symptoms compared to placebo (B = -0.07, p = .03); in the 4 g/day group, lower baseline concentrations of TNFα in LPS-stimulated PBMC were associated with significant improvement in motivational symptoms (Ρ = .71, p = .02) following treatment. In this exploratory clinical trial, daily supplementation with 4 g of ω-3-FA improves motivational symptoms in depressed individuals exhibiting an inflammatory phenotype.

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators.

Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through ω-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. Patients with MDD, body mass index >25 kg/m2, and plasma high-sensitivity C-reactive protein ≥3 µg/mL (n = 61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: EPA 1, 2, and 4 g/d, and placebo. The supplement contained EPA and DHA in a 3.9:1 ratio. Depression symptoms were assessed using the IDS-C30 scale. Plasma fatty acids and pro-resolving lipid mediators (SPMs) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. The response rate (≥50% reduction in IDS-30 score) was higher in the 4 g/d EPA arm than placebo (Cohen d = 0.53). In the 4 g/d EPA arm, responders had significantly greater increases in 18-hydroxyeicosapentaenoic acid (18-HEPE) and 13-hydroxydocosahexaenoic acid (13-HDHA) than non-responders (p < 0.05). Within the 4 g/d EPA arm, the increase in 18-HEPE was significantly associated with reductions in plasma hs-CRP concentrations (p < 0.05) and IDS-C30 scores (p < 0.01). In summary, response rates were greater among patients with MDD randomized to EPA 4 g/d supplementation and in those who showed a greater ability to activate the synthesis of 18-HEPE. The inverse association of 18-HEPE with both systemic inflammation and symptoms of depression highlights the activation of the resolution of inflammation as a likely mechanism in the treatment of MDD with ω-3 fatty acid supplementation.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

Six versus twelve weeks of Swedish massage therapy for generalized anxiety disorder: Preliminary findings.

Acute treatment of Generalized Anxiety Disorder often requires 3 months or more of care in order to optimize response. As part of an exploratory grant we have previously demonstrated that six weeks of twice-weekly Swedish Massage Therapy (SMT) was more effective than an active control in decreasing Hamilton Anxiety Rating Scale Scores (HAM-A). An additional goal of this project was to determine if an additional six weeks of twice-weekly SMT led to greater clinical and statistical benefit. We found that HAM-A scores did continue to decrease with an additional six weeks of therapy but that the greatest benefit occurred during the first versus the second 12 sessions (-9.91 vs.-3.09, t = 2.21; df = 10; p = 0.052). These preliminary findings suggest that the majority of benefit in symptom reduction occurs in the first six weeks and that six weeks of twice-weekly SMT may be sufficient for the majority of patients.

Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation.

BACKGROUND: Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients. METHODS: In a 2-site study, 61 MDD patients with body mass index >25 kg/m2 and serum high-sensitivity C-reactive protein ≥3 µg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. RESULTS: Plasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1-3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm. CONCLUSIONS: Our results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2-3, and LXB4 levels.

Clinical features and functioning of patients with minor depression.

BACKGROUND: The two essential features of minor depression are that it has fewer symptoms than major depression and that it is less chronic than dysthymia. This study describes the clinical features and functioning of outpatients with minor depression. METHODS: Subjects with minor depression (with and without a prior history of major depression) were recruited through clinical referrals and community advertising. Assessments included the Structured Clinical Interview for DSM-IV (SCID), the 17-item Hamilton Rating Scale for Depression (HAM-D), the Inventory of Depressive Symptomatology-Self Report (IDS-SR) and Clinician Rated (IDS-C) scales, the Global Assessment of Functioning (GAF) scale, the Medical Outcomes Study 36-item Short-Form scale (MOS), and the Clinical Global Impressions Severity Scale (CGI). Data from previously published studies of major depression, minor depression, and normal controls were compared to our data set. RESULTS: Minor depression is characterized primarily by mood and cognitive symptoms rather than vegetative symptoms; the functional impairment associated with minor depression is as severe as for major depression in several areas; minor depression occurs either independently of major depression or as a stage of illness during the long-term course of major depression, and minor depression patients with and without a history of major depression have similar levels of depressive severity and functional impairment. CONCLUSIONS: These findings support the notion that minor depression is an important clinical entity that fits within the larger spectrum of depressive disorders.

Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders.

OBJECTIVE: The research literature on psychosocial disability and work in mood disorders has either focused on relatively short-term course, or did not consider direct comparisons of these domains across all three of the affective subtypes of bipolar I (BP-I), bipolar II (BP-II), and unipolar major depressive disorders (UP-MDD). METHODS: Mean composite measures of psychosocial impairment and months at specific levels of overall and work impairment were compared for 158 BP-I, 133 BP-II, and 358 UP-MDD patients based on semi-structured interviews conducted during 15 years of follow-up in the NIMH Collaborative Depression Study (CDS). These are contrasted with a single month of psychosocial impairment ratings for a sample of 1787 subjects with no current psychiatric disorder. RESULTS: Patients with mood disorders experienced some degree of disability during the majority of long-term follow-up (54 to 59% of months), including 19 to 23% of months with moderate and 7 to 9% of months with severe overall impairment. Severe disability occurred a substantial percentage of time only in the specific area of work role function. BP-I patients were completely unable to carry out work role functions during 30% of assessed months, which was significantly more than for UP-MDD and BP-II patients (21% and 20%, respectively). CONCLUSIONS: These findings have public health, economic, and clinical importance, and underscore the need to reduce the chronicity and impairment associated with these three prevalent affective disorder subtypes. Interventional research is just beginning to address these challenges.

Massage Therapy for Psychiatric Disorders.

This article reviews the current state of knowledge of the role of massage therapy in the treatment of common psychiatric disorders and symptoms. It briefly discusses the prevalence of psychiatric disorders and the popularity of complementary and integrative treatments in the general population. The authors touch on the growing literature describing the biology and neurobiology of massage therapy. The impact of massage as both a therapy for major psychiatric disorders and a treatment for psychiatric symptoms is reviewed, and how massage therapists conceptualize and treat their patients with psychiatric complaints is discussed. If psychiatrists are going to partner with massage therapists, they need to understand how massage therapists' perspectives differ from those of traditional practitioners of allopathic medicine. A model of how psychiatrists and other mental health professionals can work with massage therapists to care for patients is proposed, followed by a summary of the article's key points.

Model structure for protocol adherence utilizing a manualized therapeutic massage intervention.

Background The Protocol Training and Assessment Model (Model) was developed through collaboration between Emory University School of Medicine and Atlanta School of Massage to minimize intra- and inter-therapist variability for two research massage therapist (rMT) applied intervention arms in the Massage for Cancer-Related Fatigue (MCRF) early-phase study. The Model was followed to maintain and assess protocol integrity for the study's manualized Swedish massage therapy (SMT) and light touch (LT) interventions. Methods The Model includes initial rMT training, quarterly retraining sessions, accessible resources (scripts, treatment guides, weekly research personnel meetings), and ongoing monitoring. Model efficacy was assessed by monitoring data collected at retraining sessions, through audio recording review, and through subject and rMT reporting. Results Model application resulted in a high level of intervention consistency throughout the study. Protocol-related session comment rate by subjects was 2.7%. Few study participants reported intra-rMT or inter-rMT treatment delivery differences. Observation during retraining sessions indicated massage therapists continued to adhere to protocols. Importantly rMTs increased their participation beyond core duties, suggesting additional ways to standardize subject treatment experience. Conclusions Through systematic application of the Protocol Training and Assessment Model, continuous and collaborative quality improvement discussions between scientists and research massage therapists resulted in reliable, standardized SMT and LT interventions for the MCRF early-phase study. Future research can apply the Model to support and assess consistent rMT-delivered intervention applications.

Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study.

CONTEXT: Evidence of psychosocial disability in bipolar disorder is based primarily on bipolar I disorder (BP-I) and does not relate disability to affective symptom severity and polarity or to bipolar II disorder (BP-II). OBJECTIVE: To provide detailed data on psychosocial disability in relation to symptom status during the long-term course of BP-I and BP-II. DESIGN: A naturalistic study with 20 years of prospective, systematic follow-up. SETTING: Inpatient and outpatient treatment facilities at 5 US academic centers. Patients One hundred fifty-eight patients with BP-I and 133 patients with BP-II who were followed up for a mean (SD) of 15 (4.8) years in the National Institute of Mental Health Collaborative Depression Study. MAIN OUTCOME MEASURES: The relationship, by random regression, between Range of Impaired Functioning Tool psychosocial impairment scores and affective symptom status in 1-month periods during the long-term course of illness from 6-month and yearly Longitudinal Interval Follow-up Evaluation interviews. RESULTS: Psychosocial impairment increases significantly with each increment in depressive symptom severity for BP-I and BP-II and with most increments in manic symptom severity for BP-I. Subsyndromal hypomanic symptoms are not disabling in BP-II, and they may even enhance functioning. Depressive symptoms are at least as disabling as manic or hypomanic symptoms at corresponding severity levels and, in some cases, significantly more so. At each level of depressive symptom severity, BP-I and BP-II are equally impairing. When asymptomatic, patients with bipolar disorder have good psychosocial functioning, although it is not as good as that of well controls. CONCLUSIONS: Psychosocial disability fluctuates in parallel with changes in affective symptom severity in BP-I and BP-II. Important findings for clinical management are the following: (1) depressive episodes and symptoms, which dominate the course of BP-I and BP-II, are equal to or more disabling than corresponding levels of manic or hypomanic symptoms; (2) subsyndromal depressive symptoms, but not subsyndromal manic or hypomanic symptoms, are associated with significant impairment; and (3) subsyndromal hypomanic symptoms appear to enhance functioning in BP-II.

The distinct temperament profiles of bipolar I, bipolar II and unipolar patients.

BACKGROUND: Despite a plethora of studies, controversies abound on whether the long-term traits of unipolar and bipolar patients could be differentiated by temperament and whether these traits, in turn, could be distinguished from subthreshold affective symptomatology. METHODS: 98 bipolar I (BP-I), 64 bipolar II (BP-II), and 251 unipolar major depressive disorder (UP-MDD) patients all when recovered from discrete affective episodes) and 617 relatives, spouses or acquaintances without lifetime RDC diagnoses (the comparison group, CG) were administered a battery of 17 self-rated personality scales chosen for theoretical relevance to mood disorders. Subsamples of each of the four groups also received the General Behavior Inventory (GBI). RESULTS: Of the 436 personality items, 103 that significantly distinguished the three patient groups were subjected to principal components analysis, yielding four factors which reflect the temperamental dimensions of "Mood Lability", "Energy-Assertiveness," "Sensitivity-Brooding," and "Social Anxiety." Most BP-I described themselves as near normal in emotional stability and extroversion; BP-II emerged as labile in mood, energetic and assertive, yet sensitive and brooding; MDD were socially timid, sensitive and brooding. Gender and age did not have marked influence on these overall profiles. Within the MDD group, those with baseline dysthymia were the most pathological (i.e., high in neuroticism, insecurity and introversion). Selected GBI items measuring hypomania and biphasic mood changes were endorsed significantly more often by BP-II. Finally, it is relevant to highlight a methodologic finding about the precision these derived temperament factors brought to the UP-BP differentiation. Unlike BP-I who were low on neuroticism, both BP-II and UP scored high on this measure: yet, in the case of BP-II high neuroticism was largely due to mood lability, in UP it reflected subdepressive traits. LIMITATION: We used self-rated personality measures, a possible limitation generic to the paper-and-pencil personality literature. It is therefore likely that BP-I may have over-rated their "sanguinity"; or should one consider such self-report as a reliable reflection of one's temperament? One can raise similar unanswerable questions about "depressiveness" and "mood lability." CONCLUSION: As contrasted to CG and published norms, the postmorbid self-described "usual" personality is 1) sanguine among many, but not all, BP-I; 2) labile or cyclothymic among BP-II; and 3) subanxious and subdepressive among UP. It is further noteworthy that with the exception of BP-II, the temperament scores of BP-I and MDD were within one SD from published norms. Rather than being pathological, these attributes are best conceived as subclinical temperamental variants of the normal, thereby supporting the notion of continuity between interepisodic and episodic phases of affective disorders. These findings overall are in line with Kraepelin's views and contrary to the DSM-IV formulation of axis-II constructs as being pathological and sharply demarcated from affective episodes.

A Brief Clinical Tool to Estimate Individual Patients' Risk of Depressive Relapse Following Remission: Proof of Concept.

OBJECTIVE: The authors sought to determine whether symptoms experienced by formerly depressed patients after at least 8 weeks of remission can be used to identify their risk for relapse during the next 6 months. METHOD: The study included 188 patients with major depressive disorder from the National Institute of Mental Health Collaborative Depression Study who had at least one Symptom Checklist-90 (SCL-90) assessment after at least 8 weeks of full remission from a depressive episode (defined as a value of 1 on the weekly psychiatric rating scale for all depressive conditions, recorded on Longitudinal Follow-Up Evaluation interviews). Mixed logistic regression was used to identify a set of SCL-90 items that were most predictive of relapse compared with nonrelapse within the next 6 months. RESULTS: Of 514 SCL-90 assessments completed after remission, 73 (14.2%) were followed by depressive relapse within 6 months. Seventeen SCL-90 items (including symptoms of depression, anxiety, and psychological vulnerability) significantly distinguished relapse from nonrelapse. Of these, a set of 12 symptoms maximally separated relapse from nonrelapse. Experiencing one or more of these symptoms had a sensitivity of 80.8% and a specificity of 51.2% for identifying a period in which a relapse occurred, with a positive predictive value of 21.5% and a negative predictive value of 94.2%. The relapse rate was 5.8% when none of the 12 symptoms were present, 16.4% when one to five symptoms were present, 34.1% when six to nine symptoms were present, and 72.7% when 10 or more symptoms were present. CONCLUSIONS: A brief symptom scale can be used to identify patients who, despite full remission from a depressive episode, are at substantial risk of relapse within the next 6 months, and this can be used to provide a basis for personalizing the intensity of follow-up visits.

A New Empirical Definition of Major Depressive Episode Recovery and Its Positive Impact on Future Course of Illness.

OBJECTIVE: To provide the first head-to-head test of the predictive validity of 2 resolution levels included in the current consensus definition of major depressive episode (MDE) recovery and provide an empirically based, clinically useful definition of the end of an MDE. METHOD: 322 participants entering the National Institute of Mental Health Collaborative Depression Study with MDE (diagnosed by Research Diagnostic Criteria) in 1978-1981, and followed thereafter for up to 31 years, were divided into those with 8 consecutive weeks of asymptomatic MDE recovery or residual subsyndromal depressive symptom (SSD) resolution of their index MDE. These 2 levels of recovery were defined based on weekly symptom status on all depressive conditions, assessed by Longitudinal Interval Follow-Up Evaluation (LIFE) interviews conducted every 6 months. Primary measures of validity of these 2 alternative definitions were first well interval duration and long-term depressive illness burden. Groups were also compared on clinical variables, antidepressant treatment, and psychosocial function. RESULTS: 61.2% of subjects recovered asymptomatically from their index MDE. By survival analysis, they remained free of a depressive episode relapse or recurrence 4.2 times longer than those with SSD resolution (median = 135 vs 32 weeks; χ² = 70.65; P < .0001). This was not attributable to a difference in intensity of antidepressant medication. Compared to asymptomatic recovery, SSD resolution was associated with significantly longer and more severe index MDEs, with more miscellaneous psychopathology as well as increased long-term psychosocial dysfunction and a greater depressive illness burden during the ensuing 10 or 20 years. Asymptomatic MDE resolution was a stronger predictor of time well than any of 18 other predictors, singly or combined. Eight consecutive weeks of asymptomatic recovery had 93% overlap with a 4-week definition and conferred little benefit over 4 weeks. CONCLUSIONS: Four consecutive weeks of asymptomatic recovery defines the end of an MDE and the beginning of a stable well state with improved psychosocial function. Residual symptom resolution is a continuation of an active state of the episode, not the end of an MDE.

The long-term natural history of the weekly symptomatic status of bipolar I disorder.

BACKGROUND: To our knowledge, this is the first prospective natural history study of weekly symptomatic status of patients with bipolar I disorder (BP-I) during long-term follow-up. METHODS: Analyses are based on ongoing prospective follow-up of 146 patients with Research Diagnostic Criteria BP-I, who entered the National Institute of Mental Health (Bethesda, Md) Collaborative Depression Study from 1978 through 1981. Weekly affective symptom status ratings were analyzed by polarity and severity, ranging from asymptomatic, to subthreshold levels, to full-blown major depression and mania. Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined. Finally, 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. RESULTS: Patients with BP-I were symptomatically ill 47.3% of weeks throughout a mean of 12.8 years of follow-up. Depressive symptoms (31.9% of total follow-up weeks) predominated over manic/hypomanic symptoms (8.9% of weeks) or cycling/mixed symptoms (5.9% of weeks). Subsyndromal, minor depressive, and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms (29.9% vs 11.2% of weeks, respectively). Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year. Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up, as did comorbid drug-use disorder. CONCLUSIONS: The longitudinal weekly symptomatic course of BP-I is chronic. Overall, the symptomatic structure is primarily depressive rather than manic, and subsyndromal and minor affective symptoms predominate. Symptom severity levels fluctuate, often within the same patient over time. Bipolar I disorder is expressed as a dimensional illness featuring the full range (spectrum) of affective symptom severity and polarity.

A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.

BACKGROUND: This is the first prospective longitudinal study, to our knowledge, of the natural history of the weekly symptomatic status of bipolar II disorder (BP-II). METHODS: Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospective follow-up. Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined. Predictors of chronicity for BP-II were evaluated using new chronicity measures. Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment. RESULTS: Patients with BP-II were symptomatic 53.9% of all follow-up weeks: depressive symptoms (50.3% of weeks) dominated the course over hypomanic (1.3% of weeks) and cycling/mixed (2.3% of weeks) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms combined were 3 times more common than major depressive symptoms. Longer intake episodes, a family history of affective disorders, and poor previous social functioning predicted greater chronicity. Prescribed somatic treatment did not correlate significantly with symptom chronicity. Patients with BP-II of brief (2-6 days) vs longer (> or =7 days) hypomanias were not significantly different on any measure. CONCLUSIONS: The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms. Symptom severity fluctuates frequently within the same patient over time, involving primarily symptoms of minor and subsyndromal severity. Longitudinally, BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II seems to be part of the same disease process.

A double-blind placebo-controlled trial of maca root as treatment for antidepressant-induced sexual dysfunction in women.

Objective. We sought to demonstrate that maca root may be an effective treatment for antidepressant-induced sexual dysfunction (AISD) in women. Method. We conducted a 12-week, double-blind, placebo-controlled trial of maca root (3.0 g/day) in 45 female outpatients (mean age of 41.5 ± 12.5 years) with SSRI/SNRI-induced sexual dysfunction whose depression remitted. Endpoints were improvement in sexual functioning as per the Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ). Results. 45 of 57 consented females were randomized, and 42 (30 premenopausal and 12 postmenopausal women) were eligible for a modified intent-to-treat analysis based on having had at least one postmedication visit. Remission rates by the end of treatment were higher for the maca than the placebo group, based on attainment of an ASEX total score ≤ 10 (9.5% for maca versus 4.8% for placebo), attaining an MGH-SFQ score ≤ 12 (30.0% for maca versus 20.0% for placebo) and reaching an MGH-SFQ score ≤ 8 (9.5% for maca versus 5.0% for placebo). Higher remission rates for the maca versus placebo group were associated with postmenopausal status. Maca was well tolerated. Conclusion. Maca root may alleviate SSRI-induced sexual dysfunction in postmenopausal women. This trial is registered with NCT00568126.

A double-blind, randomized controlled clinical trial comparing eicosapentaenoic acid versus docosahexaenoic acid for depression.

OBJECTIVE: To compare 2 omega-3 (n-3) preparations enriched with eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) as monotherapy for major depressive disorder (MDD) in a 2-site, placebo-controlled, randomized, double-blind clinical trial. METHOD: 196 adults (53% female; mean [SD] age = 44.7 [13.4] years) with DSM-IV MDD and a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 15 were randomized equally from May 18, 2006, to June 30, 2011, to 8 weeks of double-blind treatment with oral EPA-enriched n-3 1000 mg/d, DHA-enriched n-3 1,000 mg/d, or placebo. RESULTS: 154 subjects completed the study. Modified intent-to-treat (mITT) analysis (n = 177 subjects with ≥ 1 postbaseline visit; 59.3% female, mean [SD] age 45.8 [12.5] years) employed mixed-model repeated measures (MMRM). All 3 groups demonstrated statistically significant improvement in the HDRS-17 (primary outcome measure), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR-16), and Clinical Global Improvement-Severity Scale (CGI-S) (P < .05), but neither n-3 preparation separated from placebo (P > .05). Response and remission rates were in the range of 40%-50% and 30%, respectively, for all treatments, with no significant differences between groups. One subject receiving EPA-enriched n-3 discontinued due to worsening depression, and 1 subject receiving placebo discontinued due to an unspecified "negative reaction" to pills. CONCLUSIONS: Neither EPA-enriched nor DHA-enriched n-3 was superior to placebo for the treatment of MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00517036.

Randomized, placebo-controlled trial of fluoxetine for acute treatment of minor depressive disorder.

OBJECTIVE: Minor depressive disorder is both common and associated with significant psychosocial impairment. This study examined antidepressant treatment efficacy in a large group of patients with minor depressive disorder. METHOD: One hundred sixty-two patients with minor depressive disorder were randomly assigned to receive fluoxetine or placebo in a 12-week, double-blind study; 73% (59 of 81) of the patients in each treatment group completed the study. Patients were evaluated weekly with standard depression rating instruments and measures of psychosocial impairment. Hypotheses were tested by last-observation-carried-forward analysis of variance (ANOVA) and confirmed by mixed (random-effects) regression analysis. RESULTS: At baseline, minor depressive disorder patients were mildly to moderately depressed, with a corresponding degree of functional impairment. Over 12 weeks of treatment, both ANOVA and mixed regression showed fluoxetine to be superior to placebo as indicated by significantly greater improvement of fluoxetine-treated patients in scores on the 30-item clinician-rated Inventory of Depressive Symptomatology, the 17-item and 21-item Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Clinical Global Impression severity scale. Improvement in Global Assessment of Functioning Scale score was significantly greater for the fluoxetine group in mixed regression analysis only. Patients in both treatment groups reported a similar number and severity of adverse events during the 12-week treatment period. CONCLUSIONS: Clinicians frequently encounter minor depressive disorder either as a prodromal or residual phase of illness in major depressive disorder or as de novo minor depressive disorder episodes. Fluoxetine is significantly superior to placebo in reducing minor depressive disorder symptoms within a 12-week period. Improvement in psychosocial function with fluoxetine may take longer than 12 weeks.