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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.

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.

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 ≥ 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 ≥ 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.

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.

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.

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.

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 >= 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 >= 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.

Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) available in immediate release and controlled release (CR) formulations. Paroxetine is the most potent inhibitor of serotonin re-uptake among the now available SSRIs. Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults. The overall efficacy of paroxetine seems to be comparable to other SSRIs in the treatment of approved indications, although paroxetine treatment induces more sedation, constipation, sexual dysfunction, discontinuation syndrome and weight gain than other SSRIs. Recent data suggest that paroxetine treatment leads to increased rates of congenital malformations, although this evidence is not conclusive. Paroxetine and paroxetine CR are not indicated for use in the paediatric population and are categorised as Pregnancy Class D. In conclusion, whether the tolerability profile of paroxetine differs substantially from other new antidepressants (including other SSRIs) needs to be determined in adequately powered well-designed randomised controlled comparative clinical trials.

Delirium is a complex neuropsychiatric syndrome presenting primarily with disturbances of cognition, perception and sensorium, alertness, sleep/wake cycle, and psychomotor behavior in the context of a medical etiology. The presentation can be quite variable among patients and even within a given patient because of its waxing and waning course. This variability and overlap with other psychiatric syndromes has led to substantial underrecognition and undertreatment in clinical settings. Considering the significant morbidity and mortality associated with delirium and its tremendous economic burden, the failure to diagnose, refer, and treat such patients represents a critically important public health care issue. Clinicians should be systematically educated about delirium symptoms. Also, caregivers and family members of medically compromised patients should be educated about recognizing delirium. The use of structured diagnostic instruments and scales to follow the severity of symptoms has been an improvement in the field. However, much more research is needed into the use of such instruments and how they can be applied to clinical situations to improve the detection and treatment of delirium. Similarly, research is warranted that focuses on preventing delirium, potentially by identifying susceptible patients and intervening early. It is particularly challenging to devise cost-effective interventions for preventing and identifying delirium early in its course, given the rapid pace and resource limitations in inpatient and intensive care settings, and current data do not clearly indicate that such systems have proven benefit. Still, the indisputable health and financial costs of delirium indicate that prevention and identification should be a high priority.

On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant to possible clinical uses for this class of medications.

Clinicians are likely to encounter delirium frequently, particularly in inpatient and intensive care settings. However, delirium is underrecognized and undertreated because of its heterogeneous and fluctuating presentation and due to the limitations in resources and training in contemporary clinical settings. Translation of current knowledge about delirium into clinical practice may improve patient care and benefit public health economics. Hence, this review comprehensively discusses the phenomenology and pathophysiology of delirium and its presenting features, risk factors, differential diagnoses, assessment, prognosis, and treatment with antipsychotics; the goal is to facilitate better prevention, recognition, and treatment of delirium. Available research is reviewed, limitations of the research are discussed, and future directions for further delirium research are identified.

Although several classes of antidepressants are used to treat major depression, there is an unmet need in real clinical practice because not all patients treated with an antidepressant fully recover from their functional impairment. Hence, the development of new antidepressants based on a novel therapeutic mechanism may help in the development of more effective and ideal antidepressive agents. There is emerging evidence suggesting that the etiopathogenesis of depression involves transmitters other than the major neurotransmitters such as serotonin, norepinephrine, and dopamine. Therefore, it has consistently been suggested that an alteration in neuroprotection and synaptic plasticity is associated with the pathogenesis and therapeutic mechanism of depression. Neurotropin-3 (NT3) is an interesting protein that regulates neuronal survival, synaptic plasticity, and neurotransmission. It is widely expressed in the hippocampus and facilitates hippocampal plasticity by regulating neurogenesis. It has been also reported that an infusion of NT3 increases the level of brain-derived neurotrophic factor (BDNF) mRNA expression in the cerebral cortex and produces BDNF-like effects that induce cortical tyrosine kinase B phosphorylation. BDNF has been consistently implicated in the pathogenesis of depression and the therapeutic mechanism of antidepressants. It has also been implicated in the treatment effect of mood stabilizers such as lithium. NT3 has demonstrated its possible antidepressant effect in a learned helpless animal model. Animal studies have shown that it also modulates the neurotransmitters, serotonin and noradrenaline, which are essential in the development and treatment of depression. Therefore, further studies on the therapeutic implications of NT3 for depression are warranted and are expected for the development of newer, effective antidepressants.

This study correlates anatomic landmarks with radiographic densities and radiolucencies of the posterior pelvis, which assists in percutaneous iliosacral screw placement.Radio-opaque markers were placed on selected surfaces of cadaveric specimens and rotated under a fluoroscopic beam. Identified surfaces were described with angular measurements and anatomic characteristics.The anterior border of the S1 body is not parallel to the anterior border of the S1 ala. The anterior surface of the S1 ala is found on the inlet view ( approximately 49 degrees ) by the superimposition of the S1 and S2 alar ridges. Superior surface of the S1 ala is difficult to visualize fluoroscopically because of the highly oblique outlet angle required by fluoroscopy ( approximately 80 degrees ). The superior ridge of the S1 foramen can best be seen during an outlet view when the projection of the superior pubic symphysis is superimposed on the S2 foraminal image. Posterior bony surfaces of the ilium, foraminal region of sacrum, and sacral body are difficult to identify, as are the bony surfaces of the sacral foramina. During screw placement, the narrowest area of bone occurs in the sacral foraminal region.Use of predetermined angles for inlet and outlet views may not provide optimal visualization of relevant bony landmarks during iliosacral screw insertion. Because of variable sacral morphologies and lumbosacral lordosis, we propose using inherent landmarks to help visualize important landmarks during screw placement. Altering the fluoroscopic angle to superimpose the anterior S1 and S2 alar opacities allows the best visualization of the anterior boundary of the S1 ala. The superior bony surface of the S1 foramen is best visualized on the outlet view.

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.

Equipment design is frequently recognized as a key component in the success of GMP biologics manufacturing, but is not always implemented with full appreciation of the processing implications. In the case of mammalian cell culture, there are some recognized issues and risks that develop when transitioning to a large scale of operation. The developing demand for cell culture production capacity in the biopharmaceutical industry has led to a progressive increase in the scale of operation in the last decade. This review will provide a high level summary of the documented process difficulties unique to serum-free large scale (LS) cell culture, analyze the engineering constraints typical of these processes, and suggest some practical equipment design considerations to enhance the productivity, reliability and operability of such systems under GMP manufacturing conditions. A systems approach will be used to establish a good LS bioreactor design practice, providing a discussion on gas distribution, agitation, vessel design, SIP/CIP and control issues.

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: {"type":"clinical-trial","attrs":{"text":"NCT01777581","term_id":"NCT01777581"}}NCT01777581.

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. Trial Registration: ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01780389","term_id":"NCT01780389"}}NCT01780389

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: {"type":"clinical-trial","attrs":{"text":"NCT01829243","term_id":"NCT01829243"}}NCT01829243

Aim: To assess changes in insulin sensitivity in non-diabetic adults with schizophrenia or schizoaffective disorder treated with olanzapine or risperidone. Methods: One hundred and thirty patients were randomly assigned to 12 weeks double-blind treatment with olanzapine or risperidone. Insulin sensitivity was measured using a two-step euglycaemic, hyperinsulinaemic clamp procedure. Whole-body adiposity was measured using dual-energy X-ray absorptiometry. The primary endpoint was the within-group change from baseline in insulin sensitivity normalized to fat-free mass (Mffm/I) during the clamp procedure's low-insulin phase, using an analysis of covariance model including the covariate weight change. Results: Forty-one olanzapine-treated and 33 risperidone-treated patients completed baseline and endpoint clamp measurements. Mean Mffm/I during the low-insulin phase declined 9.0% (p = 0.226) in olanzapine-treated patients and 13.2% (p = 0.047) in risperidone-treated patients (between-group difference p = 0.354). During the high-insulin phase, Mffm/I declined 10.4% (p = 0.036) in olanzapine-treated patients and 2.1% (p = 0.698) in risperidone-treated patients (between-group difference p = 0.664). Changes in Mffm/I correlated inversely with changes in body weight and adiposity, which were generally higher in olanzapine-treated patients. Significant within-group increases in fasting glucose, but not haemoglobin A1c (HbA1c), were observed during olanzapine treatment. The fasting glucose change was not correlated with Mffm/I changes. Conclusions: Small, but statistically significant, decrements in insulin sensitivity were observed in olanzapine- and risperidone-treated patients at 1 of 2 insulin doses tested. Significant increases in fasting glucose and insulin and total fat mass were observed only in olanzapine-treated patients. Changes in insulin sensitivity correlated significantly with changes in weight or adiposity, but not with changes in glucose.

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.

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.

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.

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.

Equipment design is frequently recognized as a key component in the success of GMP biologics manufacturing, but is not always implemented with full appreciation of the processing implications. In the case of mammalian cell culture, there are some recognized issues and risks that develop when transitioning to a large scale of operation. The developing demand for cell culture production capacity in the biopharmaceutical industry has led to a progressive increase in the scale of operation in the last decade. This review will provide a high level summary of the documented process difficulties unique to serum-free large scale (LS) cell culture, analyze the engineering constraints typical of these processes, and suggest some practical equipment design considerations to enhance the productivity, reliability and operability of such systems under GMP manufacturing conditions. A systems approach will be used to establish a good LS bioreactor design practice, providing a discussion on gas distribution, agitation, vessel design, SIP/CIP and control issues.

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.

A large body of evidence suggests that the relationship between major depressive disorder (MDD) and fibromyalgia (FM) is complex. Improved understanding of this relationship promises to provide clinicians with better assessment and treatment options for both disorders.This paper reviews research on the prevalence, etiology and pathogenesis, clinical characterization, and treatment of FM and MDD, as well as studies that examined the relationship between these disorders. Studies were identified via PubMed literature search.Our findings point to substantial similarities in neuroendocrine abnormalities, psychological characteristics, physical symptoms and treatments between FM and MDD. However, currently available findings do not support the assumption that MDD and FM refer to the same underlying construct or can be seen as subsidiaries of one disease concept.New methodological and theoretical approaches may lead to a better understanding of the link between FM and MDD, and to more effective psychological and psychopharmacological therapies for FM patients. In the meantime, clinicians should carefully screen for a history of MDD in patients with FM.

Pregabalin is a structural analogue of gamma-aminobutyric acid (GABA), one of the key inhibitory neurotransmitters in the brain. It is approved by the United States Food and Drug Administration (FDA) for the treatment of pain related to diabetic peripheral neuropathy, post-herpetic neuralgia, adjuctive therapy for partial onset seizures, and fibromyalgia (US FDA, 2007). Pregabalin has also shown efficacy in other conditions for which it is used off-label, including anxiety (Feltner et al. , 2008). The current report describes the first documentation of the usefulness of pregabalin in treating lithium-induced tremor. In the case described, pregabalin was prescribed as an anxiolytic to an in-patient with treatment-refractory major depressive disorder and generalized anxiety disorder; the beneficial effect on tremor was coincidental and unexpected. However, a pilot randomized, double-blind, placebo-controlled clinical trial demonstrated the efficacy of pregabalin in the treatment of benign essential tremor (Zesiewicz et al. , 2007) and a large multicentre trial (clinicaltrials.gov NCT00584376) is currently in process to evaluate its efficacy and safety for this indication. It is plausible that pregabalin may therefore have a unique role in the treatment of patients with lithium-induced tremor, particularly considering the frequent comorbidities of anxiety in patients treated with lithium (bipolar and major depressive patients). To our knowledge, there have been no published case reports of the use of pregabalin for lithium-induced tremor. Mr A was a 65-yr-old man with a history of major depressive disorder and generalized anxiety …

Depression has been associated with impaired neurotransmission of serotonergic, norepinephrinergic, and dopaminergic pathways, although most pharmacologic treatment strategies for depression enhance only serotonin and norepinephrine neurotransmission. Current drug development efforts are aimed at a new class of antidepressants which inhibit the reuptake of all three neurotransmitters in the hope of creating medications with broader efficacy and/or quicker onset of action. The current review explores limitations of presently available antidepressants and the history and premise behind the movement to devise triple reuptake inhibitors. The evidence for and against the claim that broader spectrum agents are more efficacious is discussed. Examples of triple reuptake inhibitors in development are compared, and preclinical and clinical research with these agents to date is described.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease characterized by chronic abdominal discomfort with associated changes in stool frequency, consistency, and passage.1,2 Additional symptoms may include pain relieved by defecation, looser stools at onset of pain, abdominal distension, mucus per rectum, and sensation of incomplete evacuation.1 The prevalence of IBS is approximately 10% to 15% of the U.S. population, with a slight predominance in women.3 IBS results in significant morbidity, with patients reporting 3 times as many absences from school and work compared to those without the disorder.4 The average number of days off work per year is estimated between 8.5 to 21.6 days, with considerable medical costs and impaired quality of life.4,5 Bidirectional comorbidities between psychiatric illness and IBS are common. Studies have shown that 50% to 90% of patients in treatment for IBS have current or past psychiatric comorbidity, most commonly mood and anxiety disorders.2,6,7 It has been suggested that psychiatric comorbidity is specific to those with IBS who seek treatment, but data now indicate that the association of depressive and anxiety disorders is independent of treatment-seeking status.6,8,9 Additionally, IBS patients have been shown to have features associated with depression and anxiety, including high rates of psychosocial stress,10–12 frequent trauma and abuse history,5,13,14 high prevalence of depressive and anxiety disorders in family history,15 common heritability,16 and response to antidepressant medications.17–19 These shared characteristics between IBS and depression/anxiety as well as potentially shared pathophysiology have led authors to group IBS and other functional physical ailments (including chronic fatigue syndrome, migraine, fibromyalgia, and atypical facial pain) into “affective spectrum disorder.”20 The efficacy of antidepressant medications for IBS has been established in multiple randomized placebo-controlled trials with tricyclic antidepressants.17–19 More recent reports using selective serotonin reuptake inhibitors (SSRIs) have been mixed, and to date have consisted of case reports, open-label studies, and a few small double-blind, placebo-controlled studies.21–28 Overall, the associations between IBS and psychiatric disorders warrant further clarification, and in particular the impact of these associations on treatment expectations may be important. The current post hoc analysis evaluates whether a past history of (but not current) depressive or anxiety disorder was associated with response to treatment in a 12-week randomized controlled trial of paroxetine controlled release (CR) in the treatment of IBS; patients with current depressive or anxiety disorders were excluded from the study due to concern that paroxetine treatment of these disorders might indirectly affect gastroenterological symptoms and confound the assessment of paroxetine effects on IBS. The results of the primary efficacy analysis have been submitted for publication (P.S.M., C.U.P., S.K., et al.). For the purpose of this analysis, we decided to combine subjects with history of depressive and anxiety disorders because there was a substantial overlap between the 2 disorders, both disorders have been shown to respond to paroxetine, and we believed the combined group would increase the power to detect an effect.

Objectives: Although selective serotonin reuptake inhibitors (SSRIs) have become the standard of care for the treatment of major depressive disorder (MDD), limited data exist to support their use in MDD with atypical features. The current study investigates the efficacy of the SSRI escitalopram in an 8-week, open-label, flexible-dose, rater-blinded trial. Method: Seventeen DSM-IV MDD subjects aged from 18 through 65 years completed screening procedures, provided informed consent, and went through a minimum 2-week washout from preexisting antide-pressants except fluoxetine (a minimum 4-week wash-out). They subsequently received escitalopram (10–20 mg/day) for 8 weeks. The primary efficacy measure was a change in score from baseline to end of treatment on the Structured Interview Guide for the Hamilton Rating Scale for Depression-Seasonal Affective Disorder version (SIGH-SAD), which includes a set of items for atypical symptoms. Secondary efficacy measures were defined as changes from baseline to end of treatment in scores on the SIGH-SAD atypical symptoms subscale (consisting of 8 items specific to atypical features), Beck Depression Inventory-II, Beck Anxiety Inventory, Sheehan Disability Scale, and Epworth Sleepiness Questionnaire. The study was conducted from October 2005 to November 2006. Results: The mean age was 43.9 years, and 70.6% of subjects were women. The dropout rate was 11.8% (N = 2/17). The mean dose of escitalopram was 18.3 mg/day. The total SIGH-SAD score (mean ± SD) reduced by 53.8% from baseline (33.3 ± 8.2) to end of treatment (15.4 ± 9.4) (t = 4.24, p < .001). The atypical symptoms subscale score reduced by 44.5% from baseline (11.0 ± 4.3) to end of treatment (6.1 ± 2.8) (t = 5.26, p = .001). Ten subjects (62.5%) were classified as responders at end of treatment as defined by ≥ 50% reduction in SIGH-SAD total score. Overall, escitalopram was well tolerated. Conclusions: Our preliminary study indicates that escitalopram may be beneficial in the treatment of MDD with atypical features. Adequately powered, randomized, double-blind, placebo-controlled trials are necessary to determine the efficacy of escitalopram in this disorder. Trial Registration: clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00610506","term_id":"NCT00610506"}}NCT00610506

Only one-third of patients undergoing monotherapy with an antidepressant achieve remission of their depressive symptoms and gain functional recovery. Therefore, further exploration of antidepressant mechanisms of action is important in order to facilitate the development of antidepressants with new modes of action. Preclinical and clinical studies have demonstrated that major depression is associated with impaired inflammatory responses and deficient neuroprotection. In this regard, we propose that the second-generation tetracycline "minocycline" may hold a potential as a new treatment for major depression. Emerging findings in animal and human studies of minocycline reveal that it has antidepressant-like neuroprotective and anti-inflammatory actions, and minocycline has been shown to perform as an antidepressant in an accepted animal model (forced swimming test). Anecdotal evidence supports minocycline's efficacy for augmentation of antidepressants in major depressive disorder. The following review describes the evidence supporting the consideration of minocycline as a potential antidepressant. We suggest that minocycline may be particularly helpful in patients with depression and comorbid cognitive impairment, as well as depression associated with organic brain disease. We also describe the antinociceptive effect of minocycline and propose a role for minocycline in the treatment of patients with major depression and prominent somatic discomfort and somatoform spectrum disorders. The lack of clinical studies of minocycline for depression is noted. Further studies of the potential therapeutic mechanism of minocycline and its therapeutic implications for major depression are warranted, and may substantially contribute to the development of newer and more effective antidepressants.

Objective: To determine the extent of medical toxicology training provided in U.S. psychiatry residency programs. Medical toxicology is a newly recognized field of medicine. Many patient consultations are common to psychiatrists and medical toxicologists, including intentional drug overdoses and adverse reactions to psychotropic medications. Methods: The authors surveyed the directors of all accredited U.S. psychiatry residency programs by mail to determine how much formal training in medical toxicology, if any, is provided in these programs. Results: Eighty program directors (48.6%) responded. Replies indicated that only 4% of psychiatry residency programs were affiliated with institutions offering defined medical toxicology electives. Although residents in 65% of programs could choose to design a medical toxicology elective, this had been done in only 2 programs. Only 41% of programs responding offered specific didactic lectures on medical toxicology topics to psychiatry residents. Conclusions: The results suggest that few psychiatry residency programs have formal medical toxicology training curricula and that, in programs responding to the survey, little interaction occurs between medical toxicologists and psychiatry residents.

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.

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 and 257 males) in the Alzheimer's Disease Neuroimaging Initiative-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 the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog; P = .001) and clinical dementia rating-sum of boxes (CDR-SB; P = .003). Quadratic fit for change over time was significant for both ADAS-Cog (P = .001) and CDR-SB (P = .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 apolipoprotein E (APOE) e4 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. Trial Registration ADNI ClinicalTrials.gov identifier: NCT00106899 .

Background: Forty-eight percent of somatic symptoms encountered in the primary care setting are medically unexplained. Such symptoms have been associated with negative impact on quality of life and with functional impairment. Objective: The aim of this study was to assess the potential utility and tolerability of paroxetine for the treatment of undifferentiated somatoform disorder (USD), using the 15-item Patient Health Questionnaire (PHQ-15) to assess the severity of somatic symptoms. Methods: A prospective, open-label, 8-week pilot study of paroxetine was conducted in outpatients with USD. Data were collected at baseline and at weeks 1, 2, 4, and 8. The primary measure was the mean change in PHQ-15 total score from baseline to the end of treatment. Secondary effectiveness measures included mean changes in total scores on the Beck Depression Inventory (BDI) and the 12-item General Health Questionnaire from baseline to end of treatment. A physical examination, electrocardiography, complete blood count, blood chemistry, urinalysis, and pregnancy test (for women of childbearing potential) were performed at baseline and the end of treatment. Vital signs were measured during each visit. Adverse events (AEs) were recorded during the study and included those determined using the Systematic Assessment for Treatment Emergent Events-General Inquiry. Results: Forty-three Korean patients were screened for the study. Twenty-two patients (13 women, 9 men; mean [SD] age, 37.4 [12.4] years) were enrolled and 20 completed the study; 2 patients were lost to follow-up. The mean total score on the PHQ-15 from baseline to the end of treatment was significantly decreased (17.2 vs 4.3; P = 0.001), as was the mean total BDI score (12.8 vs. 6.3; P < 0.001). Overall, paroxetine was well-tolerated. Nausea and dry mouth were the most commonly reported treatment-emergent AEs (both, 5 [22.7%]); no serious AEs were reported. No abnormal laboratory results were observed. Conclusion: This open-label pilot study found that paroxetine had potential utility in the treatment of USD and was generally well-tolerated. These results suggest that adequately-powered, double-blind, placebo-controlled trials are warranted to more fully assess the efficacy and safety of paroxetine in the treatment of USD.