Serotonin Transporter mRNA Expression Is Reduced in the Peripheral Blood Mononuclear Cells of Subjects with Major Depression but Normal in Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) and major depression disorder (MDD) frequently co-occur. Both disorders may share common serotonergic alterations, although there is less evidence of such alterations in FM. It is also unclear as to whether these alterations are persistent over time or transient. The objectives of this study were to (i) examine the changes in mRNA expression of serotonin transporter (SERT) on the surface of peripheral blood mononuclear cells (PBMCs) in FM, MDD, and the FM + MDD subjects compared to healthy controls, and to (ii) evaluate the effect of drug treatment on SERT expression. METHODS: PBMCs were isolated from FM, MDD, FM + MDD, and control subjects. SERT expression was analyzed at the mRNA level via quantitative real-time polymerase chain reaction. Statistical analyses were performed using analyses of variance and linear mixed-effects models. RESULTS: SERT mRNA expression was significantly reduced in MDD subjects compared to controls (p < 0.001), but not in FM nor in FM + MDD subjects. Although the drug treatments improved symptoms in FM, MDD, and FM + MDD subjects, they had no significant effect on SERT mRNA expression. CONCLUSIONS: These results corroborate the role of the SERT in the pathophysiology of MDD, but not in FM, and show that the decreased mRNA expression of SERT is a persistent, rather than transient, phenomenon.

Use of a point-of-care web-based application to enhance adherence to the CANMAT and ISBD 2018 guidelines for the management of bipolar disorder.

OBJECTIVES: While clinical guidelines exist for the management of bipolar disorder (BD), there are significant challenges to their widespread dissemination and implementation in clinical practice. The Canadian Network of Mood and Anxiety Treatment Improving Patient Care and Outcomes in the Treatment of Bipolar Disorder (C-IMPACT BD) web-based application was developed for use at the point-of-care to improve adherence to guidelines for evidence-based pharmacological management of BD. METHODS: C-IMPACT BD uses a point-of-care practice assessment which, via adaptive questioning of patient-specific information, text/video descriptions of the guidelines, and pop-up prompts delivers personalized, evidence-based treatment recommendations for patients with BD. In order to inform quality improvement of the newly developed tool, a sample of Canadian physicians were invited to use the application and record its influence on their prescribing behavior. RESULTS: Of 375 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder for whom a point-of-care practice assessment was completed, a change in therapy was considered for 225 (60.0%). Prior to completing the assessment, 59.6% of these patients were receiving first-line therapy recommended for their phase of illness. Following the assessment, the overall number of patients for whom a first-line recommended therapy was being considered increased significantly to 76.9% (p = 0.0001). CONCLUSIONS: Outcomes suggest that the C-IMPACT BD web-based application has the potential to improve physician adherence to clinical treatment guidelines. Formal research investigations are warranted to explore the impact of this tool on physician prescribing behavior and patient outcomes.

Activating and Sedating Properties of Medications Used for the Treatment of Major Depressive Disorder and Their Effect on Patient Functioning.

Although the sedative and extrapyramidal side effects associated with first-generation antipsychotics are well known, some second-generation antipsychotics are also associated with substantial sedation and activation effects. In this Academic Highlights article, 4 experts on depression from the fields of psychiatry and primary care take a closer look at activation and sedation effects of atypical antipsychotics in patients with MDD. They examine the likelihood of each agent to cause these effects; the impact of these effects on patient functioning, quality of life, and treatment adherence; and the question of whether leveraging activation and sedation to address acute symptoms is ever advisable.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments.

(Reprinted by permission of SAGE Publications, Inc., from The Canadian Journal of Psychiatry 2016; 61:576-587. Copyright © 2016 by the Authors [https://doi.org/10.1177/0706743716660290]).

Functional Recovery in Major Depressive Disorder: Providing Early Optimal Treatment for the Individual Patient.

Major depressive disorder is an often chronic and recurring illness. Left untreated, major depressive disorder may result in progressive alterations in brain morphometry and circuit function. Recent findings, however, suggest that pharmacotherapy may halt and possibly reverse those effects. These findings, together with evidence that a delay in treatment is associated with poorer clinical outcomes, underscore the urgency of rapidly treating depression to full recovery. Early optimized treatment, using measurement-based care and customizing treatment to the individual patient, may afford the best possible outcomes for each patient. The aim of this article is to present recommendations for using a patient-centered approach to rapidly provide optimal pharmacological treatment to patients with major depressive disorder. Offering major depressive disorder treatment determined by individual patient characteristics (e.g., predominant symptoms, medical history, comorbidities), patient preferences and expectations, and, critically, their own definition of wellness provides the best opportunity for full functional recovery.

Functional Recovery in Major Depressive Disorder: Focus on Early Optimized Treatment.

OBJECTIVE: This article presents the case that a more rapid, individualized approach to treating major depressive disorder (MDD) may increase the likelihood of achieving full symptomatic and functional recovery for individual patients and that studies show it is possible to make earlier decisions about appropriateness of treatment in order to rapidly optimize that treatment. DATA SOURCES: A PubMed search was conducted using terms including major depressive disorder, early improvement, predictor, duration of untreated illness, and function. English-language articles published before September 2015 were included. Additional studies were found within identified research articles and reviews. STUDY SELECTION: Thirty antidepressant studies reporting predictor criteria and outcome measures are included in this review. DATA EXTRACTION: Studies were reviewed to extract definitions of predictors, outcome measures, and results of the predictor analysis. Results were summarized separately for studies reporting effects of early improvement, baseline characteristics, and duration of untreated depression. RESULTS: Shorter duration of the current depressive episode and duration of untreated depression are associated with better symptomatic and functional outcomes in MDD. Early improvement of depressive symptoms predicts positive symptomatic outcomes (response and remission), and early functional improvement predicts an increased likelihood of functional remission. CONCLUSIONS: The approach to treatment of depression that exhibits the greatest potential for achieving full symptomatic and functional recovery is early optimized treatment: early diagnosis followed by rapid individualized treatment. Monitoring symptoms and function early in treatment is crucial to ensuring that patients do not remain on ineffective or poorly tolerated treatment, which may delay recovery and heighten the risk of residual functional deficits.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Pharmacological Treatments" is the third of six sections of the 2016 guidelines. With little new information on older medications, treatment recommendations focus on second-generation antidepressants. RESULTS: Evidence-informed responses are given for 21 questions under 4 broad categories: 1) principles of pharmacological management, including individualized assessment of patient and medication factors for antidepressant selection, regular and frequent monitoring, and assessing clinical and functional outcomes with measurement-based care; 2) comparative aspects of antidepressant medications based on efficacy, tolerability, and safety, including summaries of newly approved drugs since 2009; 3) practical approaches to pharmacological management, including drug-drug interactions and maintenance recommendations; and 4) managing inadequate response and treatment resistance, with a focus on switching antidepressants, applying adjunctive treatments, and new and emerging agents. CONCLUSIONS: Evidence-based pharmacological treatments are available for first-line treatment of MDD and for management of inadequate response. However, given the limitations of the evidence base, pharmacological management of MDD still depends on tailoring treatments to the patient.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 1. Disease Burden and Principles of Care.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. This section is the first of six guidelines articles. RESULTS: In Canada, the annual and lifetime prevalence of MDD was 4.7% and 11.3%, respectively. MDD represents the second leading cause of global disability, with high occupational and economic impact mainly attributable to indirect costs. DSM-5 criteria for depressive disorders remain relatively unchanged, but other clinical dimensions (sleep, cognition, physical symptoms) may have implications for depression management. e-Mental health is increasingly used to support clinical and self-management of MDD. In the 2-phase (acute and maintenance) treatment model, specific goals address symptom remission, functional recovery, improved quality of life, and prevention of recurrence. CONCLUSIONS: The burden attributed to MDD remains high, whether from individual distress, functional and relationship impairment, reduced quality of life, or societal economic cost. Applying core principles of care, including comprehensive assessment, therapeutic alliance, support of self-management, evidence-informed treatment, and measurement-based care, will optimize clinical, quality of life, and functional outcomes in MDD.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Complementary and Alternative Medicine Treatments" is the fifth of six sections of the 2016 guidelines. RESULTS: Evidence-informed responses were developed for 12 questions for 2 broad categories of complementary and alternative medicine (CAM) interventions: 1) physical and meditative treatments (light therapy, sleep deprivation, exercise, yoga, and acupuncture) and 2) natural health products (St. John's wort, omega-3 fatty acids; S-adenosyl-L-methionine [SAM-e], dehydroepiandrosterone, folate, Crocus sativus, and others). Recommendations were based on available data on efficacy, tolerability, and safety. CONCLUSIONS: For MDD of mild to moderate severity, exercise, light therapy, St. John's wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John's wort are second-line recommendations for moderate to severe MDD. Other physical treatments and natural health products have less evidence but may be considered as third-line treatments. CAM treatments are generally well tolerated. Caveats include methodological limitations of studies and paucity of data on long-term outcomes and drug interactions.

A review of published evidence reporting on the efficacy and pharmacology of lurasidone.

INTRODUCTION: Lurasidone is a benzisothiazol derivative, approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia. Lurasidone's binding affinities are highest for the 5-HT(2A), 5-HT(7), and D(2) receptors; with lower and similar binding affinities for the norepinephrine α(2C) and 5-HT(2C) receptor subtypes. It has demonstrated efficacy in fixed-dose studies across a variable dose range (i.e., 40 - 160 mg), with a recommended starting dose of 40 mg and a maximum recommended dose of 80 mg. Lurasidone's preclinical profile is predictive not only of efficacy against psychotic and negative symptoms but also of affective symptomatology and cognitive deficits. Controlled trials are currently underway to evaluate lurasidone's efficacy in bipolar depression as well as its procognitive effects in individuals with schizophrenia. Lurasidone is administered once a day with ≥ 350 calories of food, regardless of fat content. Lurasidone is not known to adversely affect body composition, anthropometrics, metabolic and/or electrocardiographic parameters. Although prolactin elevation might be observed, prolactin-related adverse events are rarely reported. AREAS COVERED: This paper presents the pharmacodynamics and pharmacokinetics of lurasidone, and discusses its efficacy, safety and tolerability data. EXPERT OPINION: Lurasidone's simplicity of use and favorable metabolic profile are distinct advantages relative to several other agents (e.g., olanzapine). Outcomes in cognitive data analyses are awaited to determine if there is a key differentiator between lurasidone and other atypical agents with respect to efficacy. Moreover, lurasidone's efficacy in bipolar depression is awaited to determine whether this agent can be considered as a treatment alternative for depressive symptoms in adults with bipolar disorder.

The CANMAT task force recommendations for the management of patients with mood disorders and comorbid anxiety disorders.

BACKGROUND: Comorbid mood and anxiety disorders are commonly seen in clinical practice. The goal of this article is to review the available literature on the epidemiologic, etiologic, clinical, and management aspects of this comorbidity and formulate a set of evidence- and consensus-based recommendations. This article is part of a set of Canadian Network for Mood and Anxiety Treatments (CANMAT) Comorbidity Task Force papers. METHODS: We conducted a PubMed search of all English-language articles published between January 1966 and November 2010. The search terms were bipolar disorder and major depressive disorder, cross-referenced with anxiety disorders/symptoms, panic disorder, agoraphobia, generalized anxiety disorder, social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder. Levels of evidence for specific interventions were assigned based on a priori determined criteria, and recommendations were developed by integrating the level of evidence and clinical opinion of the authors. RESULTS: Comorbid anxiety symptoms and disorders have a significant impact on the clinical presentation and treatment approach for patients with mood disorders. A set of recommendations are provided for the management of bipolar disorder (BD) with comorbid anxiety and major depressive disorder (MDD) with comorbid anxiety with a focus on comorbid posttraumatic stress disorder, use of cognitive-behavioral therapy across mood and anxiety disorders, and youth with mood and anxiety disorders. CONCLUSIONS: Careful attention should be given to correctly identifying anxiety comorbidities in patients with BD or MDD. Consideration of evidence- or consensus-based treatment recommendations for the management of both mood and anxiety symptoms is warranted.

Aripiprazole augmentation in the treatment of military-related PTSD with major depression: a retrospective chart review.

BACKGROUND: In this chart review, we attempted to evaluate the benefits of adding aripiprazole in veterans with military-related PTSD and comorbid depression, who had been minimally or partially responsive to their existing medications. METHODS: A retrospective chart review of patients who received an open-label, flexible-dose, 12- week course of adjunctive aripiprazole was conducted in 27 military veterans meeting DSM-IV criteria for PTSD and comorbid major depression. Concomitant psychiatric medications continued unchanged, except for other antipsychotics which were discontinued prior to initiating aripiprazole. The primary outcome variable was a change from baseline in the PTSD checklist-military version (PCL-M) and the Beck Depression Inventory (BDI-II). RESULTS: PTSD severity (Total PCL scores) decreased from 56.11 at baseline to 46.85 at 12-weeks (p < 0.0001 from Wilcoxon signed rank test) and the depression severity decreased from 30.44 at baseline to 20.67 at 12-weeks (p < 0.0001 from Wilcoxon signed rank test). Thirty seven percent (10/27) were considered responders, as defined by a decrease in total PCL scores of at least 20 percent and 19% (5/27) were considered as responders as defined by a decrease in total BDI score of at least 50%. CONCLUSIONS: The addition of aripiprazole contributed to a reduction in both PTSD and depression symptomatology in a population that has traditionally demonstrated poor pharmacological response. Further investigations, including double-blind, placebo-controlled studies, are essential to confirm and further demonstrate the benefit of aripiprazole augmentation in the treatment of military related PTSD.

Adult ADHD and comorbid depression: A consensus-derived diagnostic algorithm for ADHD.

OBJECTIVE: Many patients present to their physician with depression as their primary symptom. However, depression may mask other comorbid disorders. This article presents diagnostic criteria and treatment recommendations (and monitoring) pertaining to the diagnosis of adult attention deficit hyperactivity disorder (ADHD), which may be missed in patients who present with depressive symptoms, or major depressive disorder (MDD). Other co-occurring conditions such as anxiety, substance use, and bipolar disorder are briefly discussed. METHODS: A panel of psychiatrist-clinicians with expertise in the area of child and adolescent ADHD and mood disorders, adult mood disorders, and adult ADHD was convened. A literature search for recommendations on the diagnosis and treatment of co-occurring conditions (MDD, anxiety symptoms, and substance use) with adult ADHD was performed. Based on this, and the panel's clinical expertise, the authors developed a diagnostic algorithm and recommendations for the treatment of adult ADHD with co-occurring MDD. RESULTS: Little information exists to assist clinicians in diagnosing ADHD co-occurring with other disorders such as MDD. A three-step process was developed by the panel to aid in the screening and diagnosis of adult ADHD. In addition, comorbid MDD, bipolar disorder, anxiety symptoms, substance use and cardiovascular concerns regarding stimulant use are discussed. CONCLUSION: This article provides clinicians with a clinically relevant overview of the literature on comorbid ADHD and depression and offers a clinically useful diagnostic algorithm and treatment suggestions.

Paroxetine versus placebo and other agents for depressive disorders: a systematic review and meta-analysis.

OBJECTIVE: To compare paroxetine with placebo and other antidepressants across multiple efficacy and tolerability outcomes. DATA SOURCES: Searches were conducted in MEDLINE (1966-2004), EMBASE (1980-2004), CINAHL (1982-2004), all Evidence-Based Medicine Reviews (1991-2004), HealthSTAR (1975-2004), BIOSIS (1980-2004), and PsycINFO (1840-2004). Medical Subject Headings (MeSH) included "paroxetine" OR "Paxil" exploded. The searches were not restricted by language, publication type, or study design. STUDY SELECTION: A study report was included if it described a randomized trial of paroxetine versus placebo or other antidepressants for patients with depressive disorders. Records were screened independently by 2 reviewers under the supervision of another reviewer. DATA EXTRACTION: Three investigators abstracted data, including study design, trial characteristics, and psychiatric assessment tools, using a prespecified form. Two investigators assessed quality of reporting using Jadad's scale. DATA SYNTHESIS: We included 62 unique randomized controlled trials. Paroxetine yielded consistently and significantly better remission (rate difference [RD]: 10% [95% CI = 6 to 14]), clinical response (RD: 17% [95% CI = 7 to 27]), and symptom reduction (effect size: 0.2 [95% CI = 0.1 to 0.3]) than placebo. Such consistency in the evidence base was not observed between paroxetine and other antidepressants. Pairwise comparisons of paroxetine and venlafaxine, mirtazapine, mianserin, or fluoxetine yielded inconsistent results across efficacy outcomes. Controlled-release paroxetine was the only antidepressant with significantly fewer dropouts due to adverse events than immediate-release paroxetine (RD: 5% [95% CI = 0.1 to 11]). CONCLUSIONS: There were no significant and valid differences between paroxetine and other antidepressants to suggest that multiple modes of action improve clinical outcomes.

Venlafaxine extended release (XR) in the treatment of panic disorder.

Panic disorder is a chronic, recurrent illness, with a lifetime prevalence of about 5%. It is associated with substantial functional impairment, and studies suggest that treatment with medication alone (and no instruction in exposure to feared and avoided situations) is less than optimal. In fact, 40%-90% of patients in long-term follow-up studies in the late 1980s and early 1990s, treated with antidepressants or high potency benzodiazepines alone, remained somewhat symptomatic. Venlafaxine extended release (XR) was effective and well tolerated in both the short-term and long-term treatment of panic disorder. In 12-week trials, venlafaxine XR was significantly more effective than placebo in achieving a panic-free state (54%-70% vs 34%-48%, p