Héctor Dueñas

The Role of Descending Inhibitory Pathways on Chronic Pain Modulation and Clinical Implications

The treatment and management of chronic pain is a major challenge for clinicians. Chronic pain is often underdiagnosed and undertreated, and there is a lack of awareness of the pathophysiologic mechanisms that contribute to chronic pain. Chronic pain involves peripheral and central sensitization, as well as the alteration of the pain modulatory pathways. Imbalance between the descending facilitatory systems and the descending inhibitory systems is believed to be involved in chronic pain in pathological conditions. A pharmacological treatment that could restore the balance between these 2 pathways by diminishing the descending facilitatory pain pathways and enhancing the descending inhibitory pain pathways would be a valuable therapeutic option for patients with chronic pain. Due to the lack of evidence for pharmacological options that act on descending facilitation pathways, in this review we summarize the role of the descending inhibitory pain pathways in pain perception. This review will focus primarily on monoaminergic descending inhibitory pain pathways and their contribution to the mechanism of chronic pain and several pharmacological treatment options that enhance these pathways to reduce chronic pain. We describe anatomical structures and neurotransmitters of the descending inhibitory pain pathways that are activated in response to nociceptive pain and altered in response to sustained and persistent pain which leads to chronic pain in various pathological conditions.

Treatment-emergent sexual dysfunction with SSRIs and duloxetine: Effectiveness and functional outcomes over a 6-month observational period

Abstract Objective. To evaluate frequencies of treatment-emergent sexual dysfunction (TESD) in patients with major depressive disorder (MDD) treated with duloxetine or selective serotonin reuptake inhibitor (SSRI) monotherapy for up to 6 months in a prospective, observational study. Methods. Sexually active MDD patients without sexual dysfunction at entry were enrolled from twelve countries (N = 1,647). TESD was assessed over the study period using the Arizona sexual experience (ASEX) scale. A priori-specified secondary 6-month clinical endpoints were also examined. Results. The frequency of TESD at 6 months with duloxetine was comparable to that with SSRI monotherapy (23.4 and 28.7%, respectively; P = 0.087). Improvements in Clinical Global Impressions of Severity (CGI-S), 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16), Integral Inventory for Depression (IID) total scores, remission and sustained remission rates were statistically significantly greater with duloxetine than SSRI monotherapy at 6 months (P < 0.001 for each), but TESD attenuated improvements in quality of life measures. Four factors were consistently significantly (P ≤ 0.05) associated with TESD at week 8 and 6 months. Conclusions. Six-month TESD rates were comparable between duloxetine and SSRIs, with greater MDD effectiveness in favour of duloxetine. Improved recognition and management of TESD may improve quality of life for MDD patients in usual clinical practice.

Caregiving for patients with Alzheimer's disease or dementia and its association with psychiatric and clinical comorbidities and other health outcomes in Brazil.

Individuals with dementia due to Alzheimers disease often receive care from family members who experience associated burden. This study provides the first broad, population‐based account of caregiving‐related health outcome burden in Brazil.

A Systematic Review of Combination Therapy with Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder, Including Patient Characteristics, Treatment Strategies, Effectiveness, and Tolerability

OBJECTIVE The purpose of this article was to systematically review the literature on stimulant and atomoxetine combination therapy, in particular: 1) Characteristics of patients with attention-deficit/hyperactivity disorder (ADHD) given combination therapy, 2) treatment strategies used, 3) efficacy and effectiveness, and 4) safety and tolerability. METHODS Literature databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, and SciVerse Scopus) were systematically searched using prespecified criteria. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers were selected for review. Exclusion criteria were comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound ADHD symptom assessment, or other concomitant medication(s) to treat ADHD symptoms. RESULTS Of the 16 publications included for review, 14 reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms of patients with ADHD. The other two publications reported findings from two prospective studies of healthy volunteers. The main reason for prescribing combination therapy was inadequate response to previous treatment. In the studies of patients with ADHD, if reported, 1) most patients were children/adolescents and male, and had a combined ADHD subtype; 2) methylphenidate was most often used in combination with atomoxetine for treatment augmentation or switch; 3) ADHD symptom control was improved in some, but not all, patients; and 4) there were no serious adverse events. CONCLUSIONS Published evidence of the off-label use of stimulant and atomoxetine combination therapy is limited because of the small number of publications, heterogeneous study designs (there was only one prospective, randomized controlled trial), small sample sizes, and geographic bias. Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success.

Efficacy and safety of duloxetine in the treatment of older adult patients with generalized anxiety disorder: a randomized, double-blind, placebo-controlled trial.

This was a flexible‐dosed study to evaluate the efficacy and safety of duloxetine 30–120 mg once daily in the treatment of generalized anxiety disorder (GAD) in older adult patients.

Frequency of treatment-emergent sexual dysfunction and treatment effectiveness during SSRI or duloxetine therapy: 8-week data from a 6-month observational study

Abstract Background. In randomised controlled trials, the frequency of treatment-emergent sexual dysfunction (TESD) in patients with major depressive disorder (MDD) at week 8 was lower with duloxetine than selective serotonin reuptake inhibitor (SSRI) therapy. Methods. This 6-month, prospective, observational study compared the frequency of TESD (using the Arizona Sexual Experience [ASEX] scale) in MDD patients treated with duloxetine or SSRI monotherapy in the first 8 weeks in normal clinical practice. Results. Physician-assessed TESD frequency at week 8 was comparable with duloxetine and SSRI monotherapy (23.9 and 26.2%, respectively; P = 0.545). Improvements in Clinical Global Impressions of Severity (CGI-S), 16-item Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR16), Integral Inventory for Depression (IID) total scores and remission rates were statistically significantly greater with duloxetine than SSRI monotherapy (P < 0.001, 0.010, <0.001, and 0.002, respectively), but TESD attenuated improvements in quality of life measures (EuroQoL questionnaire-5 dimensions [EQ-5D] and Sheehan Disability Scale [SDS] scores: ≤0.012). Several factors were significantly (P ≤ 0.05) associated with TESD at week 8 in this study. Conclusions. TESD rates with duloxetine and SSRIs at week 8 were comparable, however, significant differences in effectiveness were observed in favour of duloxetine. Antidepressant tolerability with respect to TESD must be managed to maximize remission of depressed patients.

Predictors of remission in the treatment of major depressive disorder: real-world evidence from a 6-month prospective observational study

Background This study examined potential predictors of remission among patients treated for major depressive disorder (MDD) in a naturalistic clinical setting, mostly in the Middle East, East Asia, and Mexico. Methods Data for this post hoc analysis were taken from a 6-month prospective, noninterventional, observational study that involved 1,549 MDD patients without sexual dysfunction at baseline in 12 countries worldwide. Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Depression-related pain was measured using the pain-related items of the Somatic Symptom Inventory. Remission was defined as a QIDS-SR16 score ≤5. Generalized estimating equation regression models were used to examine baseline factors associated with remission during follow-up. Results Being from East Asia (odds ratio [OR] 0.48 versus Mexico; P<0.001), a higher level of depression severity at baseline (OR 0.77, P=0.003, for Clinical Global Impression of Severity; OR 0.92, P<0.001, for QIDS-SR16), more previous MDD episodes (OR 0.92, P=0.007), previous treatments/therapies for depression (OR 0.78, P=0.030), and having any significant psychiatric and medical comorbidity at baseline (OR 0.60, P<0.001) were negatively associated with remission, whereas being male (OR 1.29, P=0.026) and treatment with duloxetine (OR 2.38 versus selective serotonin reuptake inhibitors, P<0.001) were positively associated with remission. However, the association between Somatic Symptom Inventory pain scores and remission no longer appeared to be significant in this multiple regression (P=0.580), (P=0.008 in descriptive statistics), although it remained significant in a subgroup of patients treated with selective serotonin reuptake inhibitors (OR 0.97, P=0.023), but not in those treated with duloxetine (P=0.182). Conclusion These findings are largely consistent with previous reports from the USA and Europe. They also highlight the potential mediating role of treatment with duloxetine on the negative relationship between depression-related pain and outcomes of depression.

Effectiveness of antidepressants in the treatment of major depressive disorder in Latin America.

Objective. Painful physical symptoms occur frequently in patients with major depressive disorder (MDD), and although numerous studies report the effect of antidepressants on emotional aspects of depression, few focus on their effect on physical symptoms. This observational study was conducted, in a clinical practice setting, to determine antidepressant treatment decisions and their outcome on the physical and emotional symptoms of MDD. Methods. Patients with a mean score ≥2 for pain-related items on the Somatic Symptom Inventory (SSI) were classified with painful physical symptoms (PPS +) and differentiated from the remaining patients (PPS −). Severity of depression and physical pain were determined using the 17-item Hamilton Depression Rating Scale (HAMD17) and Clinical Global Impressions of Severity Scale (CGI-S), and Visual Analog Scale (VAS), respectively. Results. At baseline, 72.6% of patients were PPS+. Compared to PPS- patients, PPS +patients were, on average, significantly more depressed at baseline (mean difference [95% CI]: HAMD17 4.6 [3.6, 5.5] and CGI-S 0.3 [0.2, 0.4]; all p<0.0001), and remained more depressed and in greater pain at endpoint (HAMD17p=0.0074, CGI-S P =0.0151, and VAS P <0.0001). In addition, fewer PPS+ patients (65.8%) achieved remission (total HAMD17≤7) compared to PPS- patients (74.6%, P =0.0180). Conclusions. Painful physical symptoms are prevalent in MDD patients, highlighting the importance of addressing both the physical and emotional symptoms of depression.

Major depressive disorder severity and the frequency of painful physical symptoms: a pooled analysis of observational studies

Abstract Objective: This retrospective post-hoc analysis of observational studies assesses the frequency of painful physical symptoms (PPS) in patients with major depressive disorder (MDD) of varied severity as may be seen in clinical practice. Methods: Observational studies of MDD that collected a clinician-reported measure of depression severity and included assessment of PPS were screened for this individual patient-level analysis. Six observational studies were included that enrolled outpatients with a diagnosis of MDD (assessed using the 17-item Hamilton depression scale, Hospital Anxiety and Depression Scale–Depression, or Inventory of Depressive Symptomatology). Measures of PPS were based on the original study assessment (modified Somatic Symptom Inventory [SSI] and Visual Analogue Scale [VAS]). Patients were divided into analysis cohorts based on the presence or absence of PPS. To model PPS status, odds ratios were calculated from logistic regression for cross-sectional analysis (main analysis) and generalized linear mixed models for longitudinal models (exploratory longitudinal analysis). Results: For the main analysis, four studies (N = 2943, 71.6% female, mean age 45.3 years) were identified. Of 2901 eligible patients, 61.7% were classified as having painful physical symptoms (PPS+). At study entry, 73.1% (957/1309) of patients in the severe category of depression, 56.8% (537/945) of those with moderate depression, and 45.6% (295/647) of those with mild depression were PPS+. The exploratory longitudinal analysis was performed using a subset (N = 2430) from the studies used in the main analysis plus two others (an additional 7984 patients, 6742 of which were modeled). The likelihood of patients that were PPS− at baseline later developing PPS was 5% to 13% greater for patients with increased depression severity (P < 0.001) and the likelihood of PPS+ patients later not having PPS was 9% to 17% less for patients with increased depression severity (P < 0.0001). Conclusions: Since this is a retrospective aggregate analysis of several observational studies, and due to missing data, care should be taken in the interpretation of these results. Despite the use of adjustment techniques, selection bias and unmeasured confounding may still be an issue for comparative analysis as not all variables were collected for all studies. For patients treated in typical care settings, PPS were associated with depression severity. However, patients with mild and moderate depression also exhibited PPS. Clinicians should be aware that PPS are present, and may warrant treatment, across depression severities.

Lost in transition: A review of the unmet need of patients with attention deficit/hyperactivity disorder transitioning to adulthood.

This review discusses the unmet needs of patients with attention deficit/hyperactivity disorder (ADHD) who are transitioning into adulthood. Although awareness and recognition of ADHD in children, adolescents, and adults have improved in recent years, there is often an interruption in management of the disorder when adolescent patients transition to adult health care services. This review has the following objectives: (1) to identify key issues patients with ADHD (with or without an early diagnosis) face during transition into adulthood; (2) to review the current clinical practice and country‐specific approaches to the management of the transition into adulthood for patients with ADHD; (3) to discuss challenges facing clinicians and their patients when drug treatment for ADHD is initiated; (4) to review current ADHD guidelines on transition management in Hong Kong, Singapore, South Korea, Turkey, and Africa; and (5) to examine economic consequences associated with ADHD. The review suggests that the transition period to adult ADHD may be an underresearched and underserved area. The transition period plays an important role regarding how ADHD symptoms may be perceived and acted upon by adult psychiatrists. Further studies are needed to explore the characteristics of the transition period. If only a fraction of adolescents go on to have mental disorders during adulthood, especially ADHD, it is crucial to identify their characteristics to target appropriate interventions at the beginning of the course of illness. There continues to be low recognition of adult ADHD and a severe lack of medical services equipped to diagnose and care for patients with ADHD transitioning from child to adult services.