GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

Correction: GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inactivation of glyceraldehyde-3-phosphate dehydrogenase by the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde.

BACKGROUND: The aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL) is an endogenous neurotoxin implicated in Parkinson's Disease. Elucidating protein targets of DOPAL is essential in understanding it's pathology. The enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a target of DOPAL. METHODS: GAPDH activity was measured via reduction of NAD+ cofactor (340 nm). Protein aggregation was assessed with SDS-PAGE methods and specific modification via chemical probes. RESULTS: Low micromolar levels of DOPAL caused extensive GAPDH aggregation and irreversibly inhibited enzyme activity. The inactivation of GAPDH was dependent on both the catechol and aldehyde moieties of DOPAL. It is suggested that Cys are modified and oxidized by DOPAL. CONCLUSIONS: The mechanism by which DOPAL modifies GAPDH can serve as a mechanistic explanation to the pathological events in Parkinson's Disease.

Comparative Effectiveness of Psychotherapy vs Antidepressants for Depression in Heart Failure: A Randomized Clinical Trial.

Importance: Heart failure (HF) affects more than 6 million adults in the US and more than 64 million adults worldwide, with 50% prevalence of depression. Patients and clinicians lack information on which interventions are more effective for depression in HF. Objective: To compare the effectiveness of behavioral activation psychotherapy (BA) vs antidepressant medication management (MEDS) on patient-centered outcomes inpatients with HF and depression. Design, Setting, and Participants: This pragmatic randomized comparative effectiveness trial was conducted from 2018 to 2022, including 1-year follow-up, at a not-for-profit academic health system serving more than 2 million people from diverse demographic, socioeconomic, cultural, and geographic backgrounds. Participant included inpatients and outpatients diagnosed with HF and depression, and data were analyzed as intention-to-treat. Data were analyzed from 2022 to 2023. Interventions: BA is an evidence-based manualized treatment for depression, promoting engagement in personalized pleasurable activities selected by patients. MEDS involves the use of an evidence-based collaborative care model with care managers providing coordination with patients, psychiatrists, and primary care physicians to only administer medications. Main Outcomes and Measures: The primary outcome was depressive symptom severity at 6 months, measured using the Patient Health Questionnaire 9-Item (PHQ-9). Secondary outcomes included physical and mental health-related quality of life (HRQOL), measured using the Short-Form 12-Item version 2 (SF-12); heart failure-specific HRQOL, measured using the Kansas City Cardiomyopathy Questionnaire; caregiver burden, measured with the Caregiver Burden Questionnaire for Heart Failure; emergency department visits; readmissions; days hospitalized; and mortality at 3, 6, and 12 months. Results: A total of 416 patients (mean [SD] age, 60.71 [15.61] years; 243 [58.41%] male) were enrolled, with 208 patients randomized to BA and 208 patients randomized to MEDS. At baseline, mean (SD) PHQ-9 scores were 14.54 (3.45) in the BA group and 14.31 (3.60) in the MEDS group; both BA and MEDS recipients experienced nearly 50% reduction in depressive symptoms at 3, 6, and 12 months (eg, mean [SD] score at 12 months: BA, 7.62 (5.73); P < .001; MEDS, 7.98 (6.06); P < .001; between-group P = .55). There was no statistically significant difference between BA and MEDS in the primary outcome of PHQ-9 at 6 months (mean [SD] score, 7.53 [5.74] vs 8.09 [6.06]; P = .88). BA recipients, compared with MEDS recipients, experienced small improvement in physical HRQOL at 6 months (mean [SD] SF-12 physical score: 38.82 [11.09] vs 37.12 [10.99]; P = .04), had fewer ED visits (3 months: 38% [95% CI, 14%-55%] reduction; P = .005; 6 months: 30% [95% CI, 14%-40%] reduction; P = .008; 12 months: 27% [95% CI, 15%-38%] reduction; P = .001), and spent fewer days hospitalized (3 months: 17% [95% CI, 8%-25%] reduction; P = .002; 6 months: 19% [95% CI, 13%-25%] reduction; P = .005; 12 months: 36% [95% CI, 32%-40%] reduction; P = .001). Conclusions and Relevance: In this comparative effectiveness trial of BA and MEDS in patients with HF experiencing depression, both treatments significantly reduced depressive symptoms by nearly 50% with no statistically significant differences between treatments. BA recipients experienced better physical HRQOL, fewer ED visits, and fewer days hospitalized. The study findings suggested that patients with HF could be given the choice between BA or MEDS to ameliorate depression. Trial Registration: ClinicalTrials.gov Identifier: NCT03688100.

Personalized treatments for depressive symptoms in patients with advanced heart failure: A pragmatic randomized controlled trial.

OBJECTIVES: Heart Failure is a chronic syndrome affecting over 5.7 million in the US and 26 million adults worldwide with nearly 50% experiencing depressive symptoms. The objective of the study is to compare the effects of two evidence-based treatment options for adult patients with depression and advanced heart failure, on depressive symptom severity, physical and mental health related quality of life (HRQoL), heart-failure specific quality of life, caregiver burden, morbidity, and mortality at 3, 6 and 12-months. METHODS: Trial design. Pragmatic, randomized, comparative effectiveness trial. Interventions. The treatment interventions are: (1) Behavioral Activation (BA), a patient-centered psychotherapy which emphasizes engagement in enjoyable and valued personalized activities as selected by the patient; or (2) Antidepressant Medication Management administered using the collaborative care model (MEDS). Participants. Adults aged 18 and over with advanced heart failure (defined as New York Heart Association (NYHA) Class II, III, and IV) and depression (defined as a score of 10 or above on the PHQ-9 and confirmed by the MINI International Neuropsychiatric Interview for the DSM-5) selected from all patients at Cedars-Sinai Medical Center who are admitted with heart failure and all patients presenting to the outpatient programs of the Smidt Heart Institute at Cedars-Sinai Medical Center. We plan to randomize 416 patients to BA or MEDS, with an estimated 28% loss to follow-up/inability to collect follow-up data. Thus, we plan to include 150 in each group for a total of 300 participants from which data after randomization will be collected and analyzed. CONCLUSIONS: The current trial is the first to compare the impact of BA and MEDS on depressive symptoms, quality of life, caregiver burden, morbidity, and mortality in patients with depression and advanced heart failure. The trial will provide novel results that will be disseminated and implemented into a wide range of current practice settings. REGISTRATION: ClinicalTrials.Gov Identifier: NCT03688100.

Opioid Overdose in the Hospital Setting: A Systematic Review.

OBJECTIVE: Our objective was to determine the percentage of opioid overdose events among medical and surgical inpatient admissions, and to identify risk factors associated with these events. METHODS: We searched PubMed and CINAHL databases from inception through July 30, 2017 and identified additional studies from reference lists and other reviews. Articles were included if they reported original research on the rate of opioid overdoses or opioid-related adverse events, and the adverse events occurred in a general medical hospital during an inpatient stay. We extracted information on study population, design, results, and risk for bias using the Newcastle-Ottawa Quality Assessment Scale. We performed this review in accordance with recently suggested standards and report our findings as per the Meta-Analyses and Systematic Reviews of Observational Studies guidelines. RESULTS: Thirteen studies met our eligibility criteria. The percentage of opioid overdoses ranged from 0.06% to 2.50% of hospitalizations. The majority of studies used only 1 method of event detection. Risk factors for overdose included older age, infancy, medical comorbidity, substance use disorder diagnosis, combining opioids with other sedatives, and admission to hospitals with higher opioid-prescribing rates. CONCLUSIONS: Opioid overdose in the inpatient setting is a serious preventable harm and is likely underestimated in much of the current literature. Improved detection methods are needed to more accurately measure the rate of inpatient opioid overdose. Refined estimates of opioid overdose should be used to drive safety and quality improvement initiatives in hospitals.

NMDA antagonists for treating the non-motor symptoms in Parkinson's disease.

Among patients with Parkinson's disease (PD), depression is prevalent and disabling, impacting both health outcomes and quality of life. There is a critical need for alternative pharmacological methods to treat PD depression, as mainstream antidepressant drugs are largely ineffective in this population. Currently, there are no recommendations for the optimal treatment of PD neuropsychiatric symptoms. Given the dual antidepressant and anti-dyskinetic effects of ketamine and other N-methyl-D-aspartate (NMDA) antagonists for PD, this review aims to examine the current evidence of NMDA antagonists for treating neuropsychiatric symptoms, including memantine, amantadine, ketamine, dizoclopine, and d-cycloserine. A comprehensive literature search was conducted using the PubMed database. We also searched the following databases up to March 1, 2018: Ovid MEDLINE, PsycINFO, CINAHL, Google Scholar, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The following keywords were used: NMDA antagonist and Parkinson's disease. Two authors independently reviewed the articles identified from the search using specific selection criteria, focusing on studies of mood, psychiatric condition, depression, cognition, and quality of life, and the consensus was reached on the 20 studies included. There is a preliminary evidence that NMDA antagonists may modulate psychiatric symptoms in PD. However, current evidence of psychiatric symptom-modifying effects is inconclusive and requires that further trials be conducted in PD. The repurposing of old NMDA antagonists, such as ketamine for depression and newer therapies, such as rapastinel, suggests that there is an emerging place for modulating the glutamatergic system for treating non-motor symptoms in PD.

The role of selective serotonin reuptake inhibitors in preventing relapse of major depressive disorder.

The objective of this review was to evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) and SSRIs compared with other treatment modalities in preventing relapse after an episode of major depressive disorder (MDD). An Ovid MEDLINE and PsycINFO search (from 1987 to August 2017) was conducted using the following terms: selective serotonin reuptake inhibitors, antidepressants, depression, prevention, prophylaxis, relapse and MDD. Using predefined criteria, two authors independently selected and reached consensus on the included studies. Sixteen articles met the criteria: 10 compared the relapse rate of selective SSRIs with placebo or other SSRIs; one discussed the effectiveness of SSRIs plus psychotherapy, two compared SSRI versus tricyclic antidepressants (TCAs), two were mainly composed of TCAs plus psychotherapy, and one compared SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs). According to the included studies, the relapse risk in adults was lower when SSRIs were combined with psychotherapy. Results comparing SSRIs and SNRIs were inconclusive. TCAs may be equally as effective as SSRIs. Atypical antidepressants (mirtazapine and St John's Wort) had no significant difference in efficacy and remission rates compared with SSRIs. Escitalopram appeared to fare better in efficacy than other SSRIs, owing to a higher prophylactic efficacy and lower side effects; however, according to the current data, this difference was not significant. To conclude, this review provides evidence that continuing SSRIs for 1 year reduces risk of MDD and relapse. Furthermore, the combination of SSRIs and cognitive behavioural therapy may effectively reduce relapse. Escitalopram appeared to yield better results and fewer side effects than did other SSRIs or SNRIs. The effectiveness in reducing relapse of SSRIs was similar to that of TCAs and atypical antidepressants.

Hydroxylated and sulfated metabolites of commonly observed airborne polychlorinated biphenyls display selective uptake and toxicity in N27, SH-SY5Y, and HepG2 cells.

Although neurotoxicity and hepatotoxicity have long been associated with exposure to polychlorinated biphenyls (PCBs), less is known about the selective toxicity of those hydroxylated PCBs (OH-PCBs) and PCB sulfates that are metabolites derived from exposure to PCBs found in indoor air. We have examined the toxicity of OH-PCBs and PCB sulfates derived from PCBs 3, 8, 11, and 52 in two neural cell lines (N27 and SH-SY5Y) and an hepatic cell line (HepG2). With the exception of a similar toxicity seen for N27 cells exposed to either OH-PCB 52 or PCB 52 sulfate, these OH-PCBs were more toxic to all three cell-types than their corresponding PCB or PCB sulfate congeners. Differences in the distribution of individual OH-PCB and PCB sulfate congeners between the cells and media, and the ability of cells to interconvert PCB sulfates and OH-PCBs, were important components of cellular sensitivity to these toxicants.

PCB95 and PCB153 change dopamine levels and turn-over in PC12 cells.

Polychlorinated biphenyls (PCB) exposure at low chronic levels is a significant public health concern. Animal and epidemiological studies indicate that low PCB body burden may cause neurotoxicity and be a risk factor for neurodegenerative diseases. In the current study, we measured the ability of two non-dioxin like PCBs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and 2,2'3,5',6-pentachlorobiphenyl (PCB95), to alter dopamine (DA) levels and metabolism using the dopaminergic PC12 cell line. Our hypothesis is that treatment of PC12 cells with non-toxic concentrations of PCB153 or PCB95 for 12 and 24 h will have different effects due to different congener structures. Levels of DA and of 3,4-dihydroxyphenylacetaldehyde (DOPAL), 3, 4-dihyroxylphenylethanol (DOPET), and 3,4-dihyroxylphenylacetic acid (DOPAC) metabolite, gene expression of the dopamine synthesis enzyme tyrosine hydroxylase (TH) and the vesicular monoamine transporter (VMAT2), and gene expression of the anti-oxidant enzymes Cu/Zn and Mn superoxide oxidase (Cu/ZnSOD, MnSOD), glutathione peroxidase (GPx) and catalase were determined. PCB153 decreased intracellular and extracellular levels of DA after 12 h exposure and this was consistent with an increase in DA metabolites. After 24 h, the level of DA in medium increased compared to the control. In contrast, PCB95 exposure increased the intracellular DA level and decreased DA in medium consistent with a down-regulation of VMAT2 expression at 12 h. After 24 h exposure, PCB95 increased DA levels in media. Expression of TH mRNA increased slightly following 12 h but not at 24 h exposure. MnSOD mRNA increased up to 6-7 fold and Cu/ZnSOD increased less than two-fold after treatment with both congeners. Catalase expression was up-regulated following 24 h exposure to PCB153 and PCB95, but GPx expression was down-regulated after 12 h exposure to PCB95 only. These results suggest that PCB153 and PCB95 are neurotoxic and affect DA turnover with structure-dependent differences between these two congeners.

The Assessment and Measurement of Wellness in the Clinical Medical Setting: A Systematic Review.

We conducted a systematic review of the published literature relating to the assessment and measurement of wellness in order to answer the following questions: 1) What is the working definition of wellness? 2) What wellness assessment instruments have been evaluated or applied in medical settings? 3) How valid, reliable, and accessible are these wellness assessment tools? The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this systematic review. Studies published from1990 to 2016 on wellness assessment were identified through Medline and PsycINFO using the following keywords: "assessment" OR "evaluation" OR "measurement" AND "wellness" OR "wellbeing." Two authors independently conducted a focused analysis then reached a consensus on 23 studies that met the specific selection criteria. This review revealed that there is a lack of uniform definition of wellness. The studies utilizing wellness assessment tools demonstrate strongest reliability values for the following instruments: Wellness Evaluation of Lifestyle, Five-factor Wellness Evaluation of Lifestyle, Perceived Wellness Survey, the Optimal Living Profile, and the Body-Mind-Spirit Wellness Behavior and Characteristic Inventory. However, there is insufficient evidence to support the clinical utility of a single particular wellness instrument. Properly defining wellness might help drive the development and validation of more precise assessment and measurement methods. This could reinforce interventions that promote wellness.

Cryptococcal meningitis in a daily cannabis smoker without evidence of immunodeficiency.

Cryptococcal meningitis is a life-threatening condition most commonly observed in immunocompromised individuals. We describe a daily cannabis smoker without evidence of immunodeficiency presenting with confirmed Cryptococcus neoformans meningitis. An investigation of cannabis samples from the patient's preferred dispensary demonstrated contamination with several varieties of Cryptococcus, including C. neoformans, and other opportunistic fungi. These findings raise concern regarding the safety of dispensary-grade cannabis, even in immunocompetent users.

Major Depression Comorbid with Medical Conditions: Analysis of Quality of Life, Functioning, and Depressive Symptom Severity.

Background: The presence of Major Depressive Disorder (MDD) is often comorbid in patients with a variety of general medical conditions (GMCs) which could lead to less favorable outcomes. Objective: The goal of this analysis is to examine functional outcomes of QOL and functioning before and after antidepressant treatment among patients with MDD with and without GMCs. Methods: We performed a secondary analysis based on the STAR*D database. The analysis included two patient groups from the STAR*D trial: 1,198 patients comorbid with MDD and GMCs (MDD + GMC) and 1,082 patients with MDD and no GMCs (MDDnoGMC), as defined by the Cumulative Illness Rating Scale. We analyzed depressive symptom severity, functioning and quality of life (QOL) before and after level 1 treatment with citalopram. Results: At baseline, the MDD + GMC group had significantly lower QOL (p < 0.001) and functioning (p = 0.001) than the MDDnoGMC group, although depressive symptom severity was not significantly different. Following antidepressant treatment, QOL, functioning and depressive symptom severity significantly improved for both MDD + GMC and MDDnoGMC groups. However, patients with MDD + GMC were more likely to experience severe impairments in QOL in (56.8% vs. 43.5% for MDDnoGMC, p < 0.001) and functioning (42.5% vs. 29.3% for MDDnoGMC, p < 0.001) following treatment. The remission rate was significantly lower for MDD + GMC (30.6% vs. 41.1% for MDDnoGMC, p < 0.001). Conclusions: Our findings suggest that antidepressant treatment had a positive impact on patients with and without GMCs. However, those with GMCs experienced not only a lower remission rate, but also continued to experience more significantly severe impairments in QOL and functioning.

Quality of life and functioning of Hispanic patients with Major Depressive Disorder before and after treatment.

BACKGROUND: Similar rates of remission from Major Depressive Disorder (MDD) have been documented between ethnic groups in response to antidepressant treatment. However, ethnic differences in functional outcomes, including patient-reported quality of life (QOL) and functioning, have not been well-characterized. We compared symptomatic and functional outcomes of antidepressant treatment in Hispanic and non-Hispanic patients with MDD. METHODS: We analyzed 2280 nonpsychotic treatment-seeking adults with MDD who received citalopram monotherapy in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression study. All subjects (239 Hispanic, 2041 non-Hispanic) completed QOL, functioning, and depressive symptom severity measures at entry and exit. RESULTS: Hispanic participants had significantly worse QOL scores at entry and exit (p < 0.01). However, after controlling for baseline QOL, there was no difference between Hispanic and non-Hispanic patients' QOL at exit (p = 0.21). There were no significant between-group differences at entry or at exit for depressive symptom severity or functioning. Both groups had significant improvements in depressive symptom severity, QOL, and functioning from entry to exit (all p values < 0.01). Patients with private insurance had lower depressive symptom severity, greater QOL, and better functioning at exit compared to patients without private insurance. LIMITATIONS: This study was a retrospective data analysis, and the Hispanic group was relatively small compared to the non-Hispanic group. CONCLUSIONS: Hispanic and non-Hispanic participants with MDD had similar responses to antidepressant treatment as measured by depressive symptom severity scores, quality of life, and functioning. Nevertheless, Hispanic patients reported significantly worse quality of life at entry.

Pain and Depression: A Systematic Review.

BACKGROUND: Pain comorbid with depression is frequently encountered in clinical settings and often leads to significant impaired functioning. Given the complexity of comorbidities, it is important to address both pain and depressive symptoms when evaluating treatment options. AIM: To review studies addressing pain comorbid with depression, and to report the impact of current treatments. METHOD: A systematic search of the literature databases was conducted according to predefined criteria. Two authors independently conducted a focused analysis of the full-text articles and reached a consensus on 28 articles to be included in this review. RESULTS: Overall, studies suggested that pain and depression are highly intertwined and may co-exacerbate physical and psychological symptoms. These symptoms could lead to poor physical functional outcomes and longer duration of symptoms. An important biochemical basis for pain and depression focuses on serotonergic and norepinephrine systems, which is evident in the pain-ameliorating properties of serotonergic and norepinephrine antidepressants. Alternative pharmacotherapies such as ketamine and cannabinoids appear to be safe and effective options for improving depressive symptoms and ameliorating pain. In addition, cognitive-behavioral therapy may be a promising tool in the management of chronic pain and depression. CONCLUSION: The majority of the literature indicates that patients with pain and depression experience reduced physical, mental, and social functioning as opposed to patients with only depression or only pain. In addition, ketamine, psychotropic, and cognitive-behavioral therapies present promising options for treating both pain and depression.

Analysis of Patient-reported Outcomes of Quality of Life and Functioning Before and After Treatment of Major Depressive Disorder Comorbid With Alcohol Use Disorders.

OBJECTIVE: Alcohol use disorders (AUDs) are common among persons with major depressive disorder (MDD) and have an adverse impact on course of illness and patient outcomes. The aim of this study was to examine whether AUD adversely impacted patient-centered outcomes in a sample of research subjects evaluated as part of a large clinical trial for depression. The outcomes of interest to this post hoc analysis are quality of life (QOL), functioning, and depressive symptom severity. METHODS: We analyzed 2280 adult MDD outpatient research subjects using data from the Sequenced Treatment Alternatives to Relieve Depression trial. We compared entry and post-selective serotonin reuptake inhibitors (SSRI) treatment QOL, functioning, and depressive symptom severity scores between 121comorbid MDD with AUD (MDD + AUD) subjects and 2159 MDD-no-AUD subjects, and also differences between subjects categorized as remitters versus nonremitters within each group at exit. RESULTS: At entry, MDD + AUD subjects reported similar QOL, functioning, and depressive symptom severity compared with the MDD-no-AUD subjects. After treatment with citalopram, both groups showed significant improvements throughout treatment; however, 36% to 55% of subjects still suffered from severely impaired QOL and functioning at exit. CONCLUSIONS: The overall study population demonstrated a significant response to treatment with large effect sizes in depressive symptom reduction, but to a lesser extent in QOL and functioning. Findings suggest that subjects with MDD + AUD benefited equally as MDD-no-AUD from treatment with selective serotonin reuptake inhibitors (SSRI) medication, yet both groups continue to experience reduced QOL and functioning after treatment. Monitoring QOL and functioning is critical to determine whether interventions that improve clinical outcomes also impact patient-centered outcomes, and our analysis suggests that there is a pressing need for innovative interventions that effectively improve these outcomes.

Trazodone for Insomnia: A Systematic Review.

OBJECTIVE: While trazodone is approved for the treatment of depression, the off-label use of this medication for insomnia has surpassed its usage as an antidepressant. In this systematic review, we examined the evidence for the efficacy and safety of trazodone for insomnia. METHODS: A literature search was conducted using MEDLINE/PubMed databases from the past 33 years (1983-2016) and the keywords insomnia, trazodone, sedative, treatment, and hypnotics. The results were restricted to English language and human subjects. All randomized clinical trials, meta-analyses, observational studies, and placebo-controlled trials regarding trazodone for the treatment of primary or secondary insomnia were reported, per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The study selection process yielded a total of 45 studies. RESULTS: Evidence for the efficacy of trazodone has been repeatedly demonstrated for primary insomnia, as well as secondary insomnia, including for symptoms that are a result of depression, dementia, and being a healthy man. Earlier studies (1980-2000) focused on utilizing trazodone at high doses (≥100mg/d) for the treatment of insomnia among the depressed population; however, since the 2000s, the utility of trazodone has been expanded to treat secondary insomnia among the non-depressed population as well. The side effects are dose-dependent, and the most common is drowsiness. CONCLUSION: A review of the literature suggests that there are adequate data supporting the efficacy and general safety of the low-dose use of trazodone for the treatment of insomnia.

Quality of Life, Functioning, and Depressive Symptom Severity in Older Adults With Major Depressive Disorder Treated With Citalopram in the STAR*D Study.

OBJECTIVE: Major depressive disorder (MDD) can substantially worsen patient-reported quality of life (QOL) and functioning. Prior studies have examined the role of age in MDD by comparing depressive symptom severity or remission rates between younger and older adults. This study examines these outcomes before and after SSRI treatment. On the basis of prior research, we hypothesized that older adults would have worse treatment outcomes in QOL, functioning, and depressive symptom severity and that nonremitters would have worse outcomes. METHODS: A retrospective secondary data analysis was conducted from the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (July 2001-September 2006). We analyzed data for 2,280 nonpsychotic adults with DSM-IV-TR-defined MDD who received citalopram monotherapy. Older adults were classified as adults aged 65 years and above. All subjects completed patient-reported QOL, functioning, and depressive symptom severity measures at entry and exit. Subjects included 106 older adults and 2,174 adults < 65. MDD remission status posttreatment was also determined. RESULTS: Both older adults and adults < 65 experienced significant improvements and medium to large treatment responses across QOL, functioning, and depressive symptom severity (P < .001). Older adults had smaller treatment effect sizes for all outcomes, particularly functioning. Conversely, mean change scores from entry to exit were equivalent across all outcomes. Remitters at exit had significantly better responses to treatment than nonremitters for the majority of outcomes. CONCLUSION: Findings suggest that older adults and younger adults have comparable treatment responses to citalopram monotherapy, with significant improvements in patient-reported depressive symptom severity, functioning, and QOL. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00021528.

Aldehyde dehydrogenase inhibition generates a reactive dopamine metabolite autotoxic to dopamine neurons.

The neurotransmitter dopamine (DA) is important for numerous biological functions, including control of movement. Oxidation of DA to highly toxic and reactive species has been hypothesized to contribute to the selective neurodegeneration observed in Parkinson's disease (PD). DA catabolism is initiated by oxidative deamination via monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL). Such metabolism can be problematic as it greatly increases the toxicity of DA by production of DOPAL, known to be a toxic and reactive intermediate. DOPAL undergoes carbonyl metabolism primarily via aldehyde dehydrogenase (ALDH) enzymes to a less toxic acid product. Previous studies from our laboratory have shown that cellular ALDH enzymes are sensitive towards products of oxidative stress and lipid peroxidation, which are thought to be elevated during PD pathogenesis. Inhibition of ALDH and the resulting accumulation of DOPAL are concerning as DOPAL is toxic to dopaminergic cells, readily modifies proteins and causes protein aggregation. In addition, pesticides with association between exposure and PD incidence can interfere with DA metabolism and trafficking and/or ALDH activity, directly or indirectly, yielding elevation of DOPAL. Therefore, impairment of carbonyl metabolism is a potential mechanistic link between cellular insult and generation of a toxic and reactive intermediate endogenous to dopamine neurons.