Marked gender differences in progression of mild cognitive impairment over 8 years.

INTRODUCTION: This study examined whether, among subjects with mild cognitive impairment (MCI), women progressed at faster rates than men. METHODS: We examine longitudinal rates of change from baseline in 398 MCI subjects (141 Females, 257 Males) in the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1), followed for up to 8 years (mean 4.1±2.5 years) using mixed effects models incorporating all follow ups (mean 8±4 visits). RESULTS: Women progressed at faster rates than men on ADAS-Cog (p=0.001) and CDR-SB (p=0.003). Quadratic fit for change over time was significant for both ADAS-Cog (p=0.001) and CDR-SB (p=0.004), and the additional acceleration in women was 100% for ADAS-Cog and 143% for CDR-SB. The variability of change was greater in women. The gender effect was greater in ApoE4 carriers. DISCUSSION: Women with MCI have greater longitudinal rates of cognitive and functional progression than men. Studies to confirm and uncover potential mechanisms appear to be warranted.

Durability of Benefit From Repeated Intravenous Lidocaine Infusions in Fibromyalgia Patients: A Case Series and Literature Review.

Fibromyalgia is a painful disorder with no curative treatments, and available medications typically provide partial relief of pain. Reported here is the effective use of serial intravenous lidocaine infusions for the chronic management of 3 patients with fibromyalgia. The details of the infusion procedure are described, and relevant literature is reviewed. Lidocaine infusions should be considered in fibromyalgia patients who are refractory to other treatments, and a positive response to 1 infusion may justify repeated infusions for chronic management.

A double-blind, placebo-controlled, parallel-group pilot study of milnacipran for chronic radicular pain (sciatica) associated with lumbosacral disc disease.

OBJECTIVE: The current study investigates whether milnacipran, an equipotent serotonin-norepinephrine reuptake inhibitor, is effective in reducing chronic radicular pain in patients (N = 11) with lumbosacral disc disease. METHOD: This study is a 10-week randomized, parallel-group, double-blind, placebo-controlled trial of milnacipran (100-200 mg/d, dosed twice a day). Subjects (enrolled from October 2010 to September 2011 through the Duke University Pain and Palliative Care Clinic, Durham, North Carolina) included patients with radiologically confirmed disc disease with nerve root compression. The primary outcome measure was radicular pain measured by visual analog scale score (VAS-Rad); patients were asked to specifically rate radicular pain ("shooting or electrical or prickly pain in 1 or both legs"). Secondary outcome measures included nociceptive low back pain by visual analog scale (VAS-Noc), Oswestry Low Back Pain Disability Questionnaire, Neuropathic Pain Questionnaire, Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey, Beck Depression Inventory, and State-Trait Anxiety Inventory. Between-group changes in outcome measures between baseline and endpoint were analyzed using Mann-Whitney U nonparametric measure of central tendency. RESULTS: Milnacipran treatment yielded statistically significant reduction in radicular pain (VAS-Rad, P = .01) and nociceptive low back pain (VAS-Noc, P = .04) compared to placebo. No statistically significant between-group differences were observed in the other secondary outcome measures. CONCLUSIONS: In this small pilot study, milnacipran treatment was associated with reduction in radicular and nociceptive low back pain in patients with lumbosacral disc disease. Larger studies of milnacipran in this population are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01777581.

Open-label milnacipran for patients with persistent knee pain 1 year or longer after total knee arthroplasty: a pilot study.

OBJECTIVE: The current study investigates whether milnacipran is effective in reducing pain and improving function in patients with persistent pain ≥ 1 year after total knee arthroplasty. METHOD: This was a 12-week open-label study of flexibly dosed milnacipran in patients (N = 5) experiencing chronic persistent knee pain ≥ 1 year following total knee arthroplasty in the absence of new injury, infection, or implant failure. Subjects were identified from October 2010 to August 2011 through the Duke University Medical Center orthopedic clinic (Durham, North Carolina), typically during 1-year postoperative follow-up visits, and were referred by their orthopedic surgeon. RESULTS: Milnacipran treatment was associated with reduction in pain according to the primary outcome measure of the visual analog scale (VAS) score for pain (effect size of 1.15) and secondary outcome measures of Knee Society Score (KSS) evaluation subscale score (effect size of 1.37) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) bodily pain subscale (effect size of 1.16) at week 12. Secondary outcome measures of functional change were mixed in such that, at week 12, the SF-36 physical functioning subscale showed improvement (effect size of 1.16), but the KSS function subscale score was just below the threshold for meaningful effect size (0.98). CONCLUSIONS: Open-label milnacipran demonstrated reduced pain and some evidence of functional improvement in this small sample of patients with chronic persistent pain 1 year or more after total knee arthroplasty such that well-powered studies are warranted.

Effects of milnacipran on neurocognition, pain, and fatigue in fibromyalgia: a 13-week, randomized, placebo-controlled, crossover trial.

OBJECTIVE: To investigate whether milnacipran is safe and effective in improving cognitive function in patients with fibromyalgia. METHOD: Patients were randomly assigned to receive milnacipran or placebo for 6 weeks, followed by a 1-week washout and then crossover to the other arm for another 6 weeks. The overall trial lasted 13 weeks and was conducted between July 2011 and May 2013. Assessments were performed at each visit. Neurocognition was measured by the Brief Assessment of Cognition (BAC) and MATRICS. Pain was assessed by the visual analog scale (VAS) for pain. Global assessment of fibromyalgia symptoms was measured by the Fibromyalgia Impact Questionnaire (FIQ) and tender point examination. Depression was assessed by the Beck Depression Inventory (BDI). Fatigue was assessed by the Fatigue Severity Scale. Functional outcome was evaluated by the Health Assessment Questionnaire. The Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales and the Patients Clinical Global Impression of Change were used to measure the global impression of severity and improvement. RESULTS: 26 subjects were screened, and 20 subjects completed the trial. The change in verbal memory (P = .001) and the composite T score (P = .044) of the BAC and the change in the attention-vigilance domain T score (P = .042) were significantly improved, but there were no differences between the drug and placebo groups. The changes in the CGI-S scores were not significant, but the changes in the Clinical Impression-Improvement (CGI-I) scores showed worsening in the placebo group at week 1 (P = .032), week 2 (P = .024), week 4 (P = .024), and week 6 (P = .60) compared to baseline. The change in FIQ scores was not significant. CONCLUSIONS: Milnacipran may have a potential role in the improvement of pain, disability, and mood. The effect of milnacipran on cognition in fibromyalgia needs further research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01829243.

Atypical depression: a comprehensive review.

Despite several decades of research, the characteristics distinguishing atypical depression from other depressive subtypes remain ambiguous. Multiple lines of evidence support the designation of atypical depression as a scientifically and clinically relevant subtype, including differences in hormonal responses, brain laterality, psychological profile and psychiatric co-morbidity and differential treatment response. The evolution of the diagnostic criteria for atypical depression has led to the designation of mood reactivity as the cardinal feature, and the research supporting this conclusion is reviewed. This paper also reviews the evidence for the drug treatment of atypical depression, with a particular focus on research related to the superior efficacy of monoamine oxidase inhibitors (MAOIs) compared with tricyclic antidepressants (TCAs). Data relevant to the efficacy of newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline (norepinephrine) reuptake inhibitors, transdermal selegiline and other new agents for atypical depression, are discussed. In summary, the diagnostic reliability and validity of atypical depression still remain elusive and open to further evolution. Currently available findings suggest that atypical depression has preferential response to MAOIs over TCAs. More data are required to determine the efficacy of newer agents relative to MAOIs and TCAs, although limited studies have shown a non-inferior efficacy and better tolerability of newer agents such as SSRIs compared with those of MAOIs and TCAs. Finally, future directions for research include further refinement of the diagnostic criteria for atypical depression, and clarification of the role of newer antidepressants in the treatment of this subtype with evidence from randomized, controlled trials.

Milnacipran: beyond a role of antidepressant.

Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) with negligible effects on any presynaptic or postsynaptic receptors. Milnacipran has unique pharmacokinetic and pharmacodynamic characteristics that distinguish it from the other marketed serotonin and norepinephrine reuptake inhibitors, venlafaxine, desvenlafaxine, and duloxetine such as equipotent serotonin and norepinephrine reuptake inhibition and a linear dose-concentration trend at therapeutic doses. The half-life of milnacipran is approximately 8 hours. In addition, milnacipran does not inhibit the cytochrome P 450 system, indicating minimal propensity for drug-drug interactions. The antidepressant efficacy of milnacipran has been clearly established in a number of randomized, double-blind, placebo-controlled clinical trials, and it has been widely used for treating major depressive disorder. Moreover, evidence suggests that milnacipran is effective and tolerable in the treatment of fibromyalgia and may have usefulness for fatigue and anxiety symptoms. The current paper reviews researches conducted to date that is relevant to the efficacy, tolerability, and mechanism of action of milnacipran in the treatment of depression, fibromyalgia, and other psychiatric syndromes. Future directions of research are also identified.

Methylphenidate extended release (OROS MPH) for the treatment of antidepressant-related sexual dysfunction in patients with treatment-resistant depression: results from a 4-week, double-blind, placebo-controlled trial.

There are limited data to indicate effective treatment strategies for antidepressant-related sexual dysfunction, in particular for patients with treatment-resistant major depression. We subanalyzed our published data whether augmentation with methylphenidate extended release (OROS MPH) improved sexual dysfunction associated with antidepressants in patients with treatment-resistant major depression. The primary efficacy measure was the change in Arizona Sexual Experiences Survey (ASEX) from baseline to end of treatment in an intent-to-treat analysis with last observation carried forward approach. There were no significant differences between the 2 groups in terms of changes in ASEX scores over time (F1,35 = 1.14; P = 0.32), although the numerical decrease in ASEX score was greater in OROS MPH (mean change, -4.5; 20.1% decrease) than in the placebo group (mean change, -0.6; 2.6% decrease). Augmentation with OROS MPH showed no statistically significant benefit in antidepressant-related sexual dysfunction, although addition of OROS MPH to antidepressants did not worsen preexisting sexual dysfunction. Adequately powered controlled trials are needed to fully evaluate the efficacy of OROS MPH in this area.

Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants.

Chronic fatigue syndrome (CFS) is characterized by chronic, medically unexplained fatigue associated with effort- and stress-intolerance, widespread pain, and impairment in sleep and concentration. Although this constellation of symptoms is highly prevalent in clinical practice, the pathophysiological mechanisms underlying CFS are poorly understood. Current evidence indicates similarities in symptomatology, and possibly etiology and pathogenesis, between CFS and depression. Additionally, there is significant overlap between CFS and the syndrome of fibromyalgia for which antidepressants have shown consistent efficacy. Data regarding antidepressant treatment of CFS is less copious and less uniformly positive, such that antidepressant use in CFS remains controversial. The current review aims to summarize available data related to antidepressants and other psychotropic agents in CFS to provide a platform for clinicians to make decisions in their treatment of this challenging syndrome. We identified relevant studies through a PubMed literature search with a combination of the following search terms: 'fatigue,' 'depression,' 'antidepressant,' 'etiology' (e.g., 'neurobiology,' 'neurotransmitter,' 'genetic'), 'diagnosis,' and 'treatment' (e.g., 'antidepressant' plus the specific name). In addition, studies were also identified via the reference sections of retrieved articles. The authors thoroughly reviewed major findings from the scanned literatures and eventually synthesized them, providing summary, interpretation, and future directions.

History of depressive and/or anxiety disorders as a predictor of treatment response: a post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release in patients with fibromyalgia.

BACKGROUND: Despite of a high comorbidity of depressive and/or anxiety disorders with fibromyalgia, information on the clinical implications of this comorbidity is limited but antidepressants are commonly prescribed to treat fibromyalgia in clinical practice. We investigated whether a history of depressive and/or anxiety disorders was associated with response to paroxetine controlled release (CR) in the treatment of fibromyalgia. METHODS: One hundred sixteen (116) fibromyalgia subjects were randomized to receive paroxetine CR or placebo for 12 weeks. The primary outcome was treatment response defined as >or=25% reduction in the Fibromyalgia Impact Questionnaire (FIQ) score. In multivariate logistic regression, we determined if a history of depression and/or anxiety disorders was an independent predictor of response to paroxetine CR. RESULTS: In logistic regression, the history of depression and/or anxiety did not predict treatment response as measured by >or=25% reduction in Fibromyalgia Impact Questionnaire (FIQ) score (OR=0.66, 95% CI=.29-1.49, Wald=0.97, p=0.32), while the drug status (paroxetine CR) was significantly associated with treatment response (OR=2.57, CI=1.2-5.61, Wald=5.5, p=0.02). CONCLUSION: A significant proportion of patients with fibromyalgia had a history of anxiety and or depressive disorders. However response to treatment of fibromyalgia symptoms with paroxetine CR was not associated with a history of depressive and/or anxiety disorders. Our findings need to be confirmed in more adequately-powered and well-designed subsequent studies.

History of early abuse as a predictor of treatment response in patients with fibromyalgia: a post-hoc analysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release.

OBJECTIVES: We conducted a post-hoc analysis to determine whether a history of physical or sexual abuse was associated with response to treatment in a double-blind, randomized, placebo-controlled trial of paroxetine controlled release (CR) in fibromyalgia. METHODS: A randomized, double-blind, placebo-controlled trial of paroxetine controlled release (CR) (dose 12.5-62.5 mg/day) was conducted in patients with fibromyalgia for 12 weeks. A total of 112 subjects provided complete information on childhood history of abuse that was recorded using the Sexual and Physical Abuse Questionnaire and randomized to treatments. Outcome evaluations in the abuse subgroup were identical to those in the entire sample. Health Status was determined using the 36-Item Short Form Health Survey (SF-36), the Sheehan Disability Scale (SDS), and the Perceived Stress Scale (PSS). Fibromylagia symptom severity was determined using the Fibromyalgia Impact Questionnaire (FIQ) and the Visual Analogue Scale for Pain (VAS). The primary outcome was treatment response defined as > or = 25% reduction in the FIQ-total score. Secondary outcomes include changes in scores on the Clinical Global Impression-Severity and Improvement (CGI-S and CGI-I respectively) and SF-36. RESULTS: The rate of childhood physical and/or sexual abuse was 52.7% (n=59). The baseline characteristics (health status, perceived stress, symptom severity) were not associated with abuse history. In logistic regression, the history of abuse did not predict treatment response as measured by > or = 25% reduction in FIQ-total score (OR = 1.16, 95% CI = 1.18-1.60, P = 0.35), while the drug status (paroxetine CR) was significantly associated with treatment response (OR = 2.51, 95% CI = 1.12-5.64, P = 0.02). Abuse history did not predict CGI-I (P = 0.32) or CGI-S (P = 0.74) improvements during treatment. After 12 weeks of treatment, subjects with sexual abuse history showed significantly lower mean change in health status (SF-36) than those without sexual abuse history (P = 0.04). CONCLUSIONS: Although, a significant proportion of patients with fibromyalgia reported a history of abuse, it does not appear to have any significant clinical correlates at baseline. History of abuse did not predict response to treatment in patients with fibromyalgia participating in a controlled trial of paroxetine controlled release. Prospective, well-designed studies are needed to confirm whether selective serotonin uptake inhibitors are effective in patients with fibromyalgia irrespective of their abuse history.

Desvenlafaxine, a serotonin-norepinephrine uptake inhibitor for major depressive disorder, neuropathic pain and the vasomotor symptoms associated with menopause.

Desvenlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI) developed by Wyeth, is a novel salt form of the isolated major active metabolite of the antidepressant venlafaxine. Desvenlafaxine was developed as a slow-release tablet formulation and rapidly penetrates the brain upon administration supporting its direct effects on neuronal systems of the brain. Unlike various other antidepressants including venlafaxine, desvenlafaxine is not metabolized by cytochrome p450 (CYP) enzyme pathways and is associated with minimal inhibition of CYP enzymes. This feature results in a comparatively low risk of drug-drug interaction and consistent intra-individual and inter-individual pharmacokinetic profiles. Desvenlafaxine has been recently approved by the US FDA for the treatment of major depressive disorder (MDD) based on a series of randomized, double-blind, placebo-controlled clinical trials indicating efficacy and safety for patients with MDD. Studies have also supported the potential utility of desvenlafaxine in the treatment of vasomotor symptoms of menopause, anxiety symptoms and painful physical symptoms. However, concerns including mixed efficacy and adverse events need to be further explored in future studies.

Innovations in clinical research design and conduct in psychiatry: shifting to pragmatic approaches.

The classically structured clinical trial does not offer enough flexibility to make use of continuously emerging knowledge that is generated as the trial progresses. In this regard, there are consistent issues impeding effective psychiatric research, including limitations in efficiency, difficulty demonstrating significant differences between treatment arms, poor external validity, and ethical constraints. For example, research in the field of psychiatry shows that it is growing increasingly more challenging to demonstrate superiority of interventions to placebo in part related to the increasing placebo response rates. Various design innovations and other tricks of the trade have surfaced to improve sensitivity towards detecting drug-placebo differences and reduce sources of bias in psychiatric research. Diverse strategies have been developed to address these obstacles and improve the outcomes of clinical research in psychiatry. The current review highlights many of these innovations and describes examples of their practical use, mainly focusing on the study design and conduct perspectives. In the study design issues, adaptive, equipoise stratified, sequential parallel and effectiveness design will be explored. The proper strategies for pragmatic and ethical conduction of clinical trials will be also discussed in-depth.

Does pregabalin have neuropsychotropic effects?: a short perspective.

Pregabalin is a newly developed synthetic gamma-aminobutyric acid (GABA) that is approved for the treatment of fibromyalgia and several neuropathy. It has been proven to show analgesic, anxiolytic, anticonvulsant and sleep enhancement effects, which could be applicable in the treatment of a variety of psychiatric disorders. There have been consistent reports that unexplained somatic symptoms (i.e., pain) may be a part of psychiatric disorders such as major depressive disorder (MDD) and anxiety disorders. Previous researches have also suggested the possible therapeutic potential of anticonvulsants as augmentation therapy or monotherapy in the treatment of mood disorders and anxiety disorders. Hence this short perspective tries to prompt and facilitate a shifting of researchers' attention to potential neuropsychotropic drug role of pregabalin to treat a wide range of neuropsychiatric disorders.

Effectiveness of antidepressant treatments in pre-menopausal versus post-menopausal women: a pilot study on differential effects of sex hormones on antidepressant effects.

The incidence or recurrence of major depression is greatly increased in women during the transition to and after menopause and hormonal changes occurring during these periods are thought to play an important role in depressive recurrence. It has been also suggested that a chronic hypoestrogenic state may reduce the response to antidepressant drugs, but whether or not, and the extent to which hormonal changes related to menopause influence the response to antidepressant drugs, is yet to be determined. Thirty-nine female patients (n=17 in pre-menopause; n=22 in post-menopause) with major depressive disorder (MDD) based on DSM-IV criteria, who were not on hormonal replacement therapy, participated in the study in order to prospectively evaluate the effect of menopausal status and its hormonal correlates on the effectiveness of antidepressant treatment for 6weeks. The Hamilton Depression Rating Scale-17 item (HAMD), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression Severity scale (CGI-S) were administered at baseline, week 1, week 3, and week 6. The CGI-I scale was also assessed at weeks 1, 3, and 6. After controlling for age, age at onset, baseline symptom severity, antidepressant dosage and hormonal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), post-menopausal women showed a poor response to antidepressants over 6weeks of treatment, compared to the response of pre-menopausal women. Old age and high levels of FSH were also associated with the efficacy of antidepressants in post-menopausal women. In conclusion, sex hormones are known to interact with serotonergic, noradrenergic and dopaminergic systems. Despite methodological limitations, our study suggests that menopausal status and old age are predictors of a poor response to antidepressant treatment. Furthermore, the FSH may interfere with the mechanism of action of the antidepressant agents. Hence, larger, randomized and controlled trials are warranted to expand our understanding of this area.

Pregabalin augmentation of antidepressants in patients with accident-related posttraumatic stress disorder: an open label pilot study.

This study evaluated the efficacy of pregabalin augmentation of antidepressant treatment in patients with posttraumatic stress disorder (PTSD). Nine patients meeting Diagnostic and Statistical Manual, fourth edition criteria for PTSD who were on stable doses of antidepressants were treated open label with flexibly dosed pregabalin for 6 weeks. All patients were assessed with the Short PTSD Rating Interview, Montgomery-Asberg Depression Rating Scale, Patient Global Impression-severity, Visual Analog Scale-pain, and Sheehan Disability Scale at baseline and weeks 2, 4, and 6. Significant reductions were observed in all effectiveness measures from week 4 to the end of the study. In particular, the numerical improvement of the Visual Analog Scale-pain score was most robust (-53.4%, P=0.007). Pregabalin augmentation was effective and well tolerated during the study. Our findings warrant adequately powered, placebo-controlled clinical trials to confirm the usefulness of pregabalin augmentation of antidepressants in patients with PTSD.

The impact of the CONSORT statement on reporting of randomized clinical trials in psychiatry.

To determine whether the CONSORT recommendations influenced the quality of reporting of randomized controlled trials (RCTs) in the field of psychiatry, we evaluated the quality of clinical trial reports before and after the introduction of CONSORT statement. We selected seven high impact journals and retrieved the randomized, clinical trials in the field of psychiatry during the period of 1992-1996 (pre-CONSORT) and 2002-2007 (post-CONSORT). Among the total 5201 articles screened, 736 were identified and entered in our database. After critical review of the publications, 442 articles met the inclusion and exclusion criteria. The CONSORT Index (sum of 22 items of the checklist) during the post-CONSORT period was significantly higher than that during the pre-CONSORT period. However, over 40% of post-CONSORT studies did not adhere to CONSORT statement for reporting the process of randomization, and details of the process for obtaining informed consent were still insufficient. Furthermore, adherence to the CONSORT guidelines of reporting how blinding was accomplished and evaluated actually decreased after publication of the CONSORT statement. Although the overall quality of reporting on psychiatric RCTs generally improved after publication of the CONSORT statement, reporting the details of randomization, blinding, and obtaining informed consent remain insufficient.

Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise.

The precise mechanisms of pain perception and transmission in the central nervous system have not been fully elucidated. However, extensive data support a role for the monoamine neurotransmitters, serotonin and norepinephrine, in the modulation of pain. Experiments with animal models of pain indicate that noradrenergic interventions, and to a lesser extent serotonergic interventions, reduce pain-related behavior. This is supported by data from clinical trials in humans in which antidepressants have been shown to reduce pain and functional impairment in central and neuropathic pain conditions. These effects are particularly well-studied in trials with serotonin-norepinephrine reuptake inhibitors (SNRIs), which have provided a useful tool in the clinician's arsenal, particularly considering the limitations of other classes of pain medications such as opioids, anti-inflammatories, and anticonvulsants (i.e., limited efficacy, safety and tolerability issues). Moreover, painful physical symptoms are frequently comorbid with major psychiatric disorders such as major depressive disorder and anxiety disorders. This paper reviewed and summarized the rationale and potential role of SNRIs for the control of pain including clinical and preclinical background. Currently evidence does not definitely support a role of the SNRIs, while limited data propose a putative promise of SNRIs in the treatment of pain related disorders including fibromyalgia and depressed patients with multiple somatic complaints. More researches are warranted to generalize currently available preliminary evidences.