Treatment-resistant depression (TRD) represents a considerable global health concern. The goal of the InSight study was to investigate the prevalence of TRD and to evaluate its clinical characterization and management, compared with nonresistant depression, in primary care centres.
Physicians completed a case report on a consecutive series of patients with major depressive disorder (n = 1212), which captured patient demographics and comorbidity, as well as current and past medication.
Using failure to respond to at least 2 antidepressants (ADs) from different classes as the definition of TRD, the overall prevalence was 21.7%. There were no differences in prevalence between men and women or among ethnicities. Patients with TRD had longer episode duration, were more likely to receive polypharmacy (for example, psychotropic, lipid-lowering, and antiinflammatory agents), and reported more AD related side effects. Higher rates of disability and comorbidity (axes I to III) were associated with treatment resistance. Obesity and being overweight were also associated with treatment resistance. While the selection and sequencing of pharmacotherapy by family physicians in this sample was in line with recommendations from evidence-based treatment guidelines, the wait time to make a change in treatment was 6 to 8 weeks in both groups, which exceeds guideline recommendations.
These real-world data demonstrate the high prevalence of TRD in primary care settings, and underscore the substantial burden of illness associated with TRD.
treatment-resistant depression; prevalence; risk factors; primary care
Cognitive function in older adults may be affected by multiple factors such as sex hormone levels, metabolic disturbances and neuropsychiatric illness. However, relatively few studies have tested the associations between these factors and cognitive function in a single sample. A cross-sectional analysis was conducted to examine the association between sex hormones, metabolic parameters, and psychiatric diagnoses with verbal memory in non-demented older men.
Participants included 112 men (mean age = 61.3 years) from the Baltimore Epidemiologic Catchment Area Follow-Up Study who completed measures of blood sex hormone levels, metabolic parameters (e.g. lipid profiles), and verbal memory.
Higher levels of serum sex hormone binding globulin (SHBG) were associated with lower delayed verbal memory scores [standardized coefficients (beta) = −0.19, t = −2.07, df = 1, 105, p = 0.04)], and higher body mass index (BMI) was associated with better immediate (beta = 0.21, t = 2.41, df = 1,105, p = 0.02) and delayed (beta = 0.22, t = 2.46, df = 1,105, p = 0.02) verbal memory performance following adjustment for age, education, and psychiatric disorders. There was an inverse correlation between SHBG levels and BMI (Pearson’s r = −0.37, n = 112, p < 0.001). Estimated free testosterone levels revealed curvilinear associations with verbal memory performance.
Our data suggest that higher SHBG levels are associated with worse verbal memory, whereas a higher BMI is associated with better verbal memory in older men. Higher SHBG levels due to lower adiposity may be a risk factor for cognitive dysfunction. The mechanisms linking SHBG to cognitive function have yet to be elucidated.
depression; cognitive dysfunction; psychosocial functioning; antidepressants
Bariatric surgery is the most effective therapy for severe obesity. People with bipolar disorder have increased risk of obesity, yet are sometimes considered ineligible for bariatric surgery due to their bipolar disorder diagnosis. This study aimed to determine if bariatric surgery alters the psychiatric course among stable patients with bipolar disorder.
A matched cohort study (2006–2009) with mean follow-up of 2.17 years, was conducted within Kaiser Permanente Northern California, a group practice integrated health services delivery organization that provides medical and psychiatric care to 3.3 million people. Participants were 144 severely obese patients with bipolar disorder who underwent bariatric surgery, and 1,440 control patients with bipolar disorder, matched for gender, medical center, and contemporaneous health plan membership. Controls met referral criteria for bariatric surgery. Hazard ratio for psychiatric hospitalization, and change in rate of outpatient psychiatric utilization from baseline to Years 1 and 2, were compared between groups.
A total of 13 bariatric surgery patients (9.0%) and 153 unexposed to surgery (10.6%) had psychiatric hospitalization during follow-up. In multivariate Cox models adjusting for potential confounding factors, the hazard ratio of psychiatric hospitalization associated with bariatric surgery was 1.03 [95% confidence interval (CI) 0.83–1.23]. In fully saturated multivariate general linear models, change in outpatient psychiatric utilization was not significantly different for surgery patients versus controls, from baseline to Year 1 (−0.4 visits/year, 95% CI: −0.5 to 0.4) or baseline to Year 2 (0.4 visits/year, 95% CI: −0.1 to 1.0).
Bariatric surgery did not affect psychiatric course among stable patients with bipolar disorder. The results of this study suggest that patients with bipolar disorder who have been evaluated as stable can be considered for bariatric surgery.
bipolar disorder; obesity; psychiatric utilization
This study aimed to determine the distributions of the age at onset (AAO) in patients with major depressive disorder (MDD) using admixture analysis and to determine the clinical differences between subgroups with different AAO.
Participants were administered the Mini-International Neuropsychiatric Interview and the Montgomery–Asberg Depression Rating Scale to obtain clinical data. Admixture analysis was performed using the STATA module DENORMIX to identify subgroups characterized by differences in AAO.
The best fit model was the three-component model with the following means, standard deviations and proportions: 14.60 (3.75) years (49.1%), 29.15 (6.75) years (34.1%) and 46.96 (6.06) years (16.8%) (χ2=3.64, 2 df, P=.162). The three subgroups were divided by AAO of 22 and 40. After controlling for duration of illness, there were no significant differences between the three subgroups in terms of gender and family history. However, the early-onset subgroup was significantly more likely to report being single compared to the intermediate- and late-onset groups. The proportion of individuals meeting criteria for lifetime comorbid panic disorders and obsessive–compulsive disorder did not differ significantly between the AAO groups. However, there was a trend for higher incidence of generalized anxiety disorder in the early- and intermediate-onset compared to the late-onset subgroup (43.4% and 41.9% vs. 30.0%, P=.095). Furthermore, the early-onset group reported a higher incidence of attention-deficit/hyperactivity disorder (5.1% vs. 1.7% and 1.2%, P=.085) diagnosis, although this was also not statistically significant. In addition, there was a trend for higher rate of lifetime substance use in the early-onset group compared to the intermediate- and late-onset groups (18.9% compared to 12.4% and 10.0%, respectively; P=.061).
Our study identified clinically different AAO subgroups in individuals suffering from MDD. The subgroups may reflect different underlying neurobiological mechanisms involved.
A bidirectional relationship exists between diabetes mellitus (DM) and major depressive disorder (MDD), with depression commonly reported in both type 1 DM (T1DM) and type 2 DM (T2DM), and depressive symptoms associated with a higher incidence of diabetes. However, how the two conditions are pathologically connected is not completely understood. Similar neurophysiological abnormalities have been reported in both DM and MDD, including elevated electroencephalographic (EEG) activity in low-frequency slow waves and increased latency and/or reduced amplitude of event-related potentials. It is possible that this association reflects some common underlying pathology, and it has been proposed that diabetes may place patients at risk for depression through a biological mechanism linking the metabolic changes of DM to changes in the central nervous system. In this review we will discuss EEG abnormalities in DM, as well as the biological mechanisms underlying various EEG parameters, in order to evaluate whether or not a common EEG biosignature exists between DM and MDD. Identifying such commonalities could significantly inform the current understanding of the mechanisms that subserve the development of the two conditions. Moreover, this new insight may provide the basis for informing new drug discovery capable of mitigating and possibly even preventing both conditions.
electroencephalography; event-related potential; diabetes mellitus; major depressive disorder
Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders.
Objective. This study explores the relationship between depressive symptoms, as measured by the PHQ-9 depression screen and blood glucose levels among patients with diabetes enrolled in Gold Choice, a Medicaid managed care program for individuals with mental illness and/or substance abuse. Methods. The PHQ-9 was mailed to 454 Gold Choice members and a questionnaire was mailed to their physicians requesting current HbA1c% and fasting blood glucose (FBG) levels. The pearson product-moment correlation was used to describe the association between PHQ-9 scores and FBG levels.
Results. The PHQ-9 response rate was 55% (N = 249). Laboratory results were received for 141 patients. The correlation between FBG and PHQ-9 scores was modest but statistically significant: r = 0.21
, P = 0.015.
Conclusion. A statistically significant association was found between FBG and PHQ-9 depression scores. This finding supports current recommendations that physicians be alert to depressive symptoms among patients with diabetes or impaired glucose metabolism.
We aimed to review and synthesize results reporting on the maintenance efficacy of Aripiprazole in adults with bipolar I disorder. Aripiprazole is FDA approved for the acute and maintenance treatment of bipolar I disorder. Aripiprazole’s efficacy during the long-term treatment of bipolar disorder is supported by extension of acute phase studies and long-term (ie, 100-week) double-blind placebo controlled recurrence prevention registration trials. Aripiprazole is not established as efficacious in the acute or maintenance treatment of bipolar depression. Moreover, aripiprazole’s efficacy during the acute or maintenance phase of bipolar II disorder has not been sufficiently studied. Aripiprazole has a relatively lower hazard for metabolic disruption and change in body composition when compared to other atypical agents (eg, olanzapine, quetiapine). Moreover, aripiprazole has minimal propensity for sedation, somnolence and prolactin elevation. Aripiprazole is associated with extrapyramidal side effects, notably akathisia, which in most cases is not severe or treatment limiting. Future research vistas are to explore aripiprazole’s efficacy in bipolar subgroups; recurrence prevention of bipolar depression; and in combination with other mood stabilizing agents.
aripiprazole; bipolar disorder; maintenance; pharmacology
Bipolar disorder is a multidimensional illness typified by fluctuating periods of depression and mania, cognitive dysfunction, abnormal circadian rhythms, and multiple comorbid psychiatric and general medical conditions. Indefinite pharmacological treatment is often required, yet the modest effects of available treatments and frequent difficulties with tolerability and adherence present complex challenges to patients. Long-acting injectable medications offer a therapeutic alternative to oral mood stabilizers and may help facilitate long-term treatment adherence. This article will provide a succinct review of the latest data on the use of long-acting injectable risperidone (LAR) during the maintenance phase treatment of bipolar disorder. The specific role of LAR in comparison to other atypical antipsychotics, and the limitations of available studies will be discussed from the perspectives of efficacy, tolerability, and sequential positioning in treatment guidelines.
adherence; bipolar disorder; long-acting risperidone; maintenance phase; risperidone
Treatment of bipolar patients is often complicated by metabolic abnormalities such as obesity, diabetes, and dyslipidemia. We therefore evaluated the prevalence of these abnormalities and their correlates, in bipolar I patients, at the time of commencement of pharmacological treatment for acute mood episodes.
The study cohort consisted of 184 bipolar I patients hospitalized for treatment of acute mood episodes. Socio-demographic and clinical variables were noted and metabolic parameters, including body mass index, fasting plasma glucose, fasting total cholesterol, and current treatment(s) for diabetes and/or dyslipidemia were measured before initiating medication(s).
Fifty-six (30.4%) subjects met our criteria for obesity; 80 (43.5%) had hyperglycemia, with 8 (4.3%) receiving anti-diabetic medication; and 38 (20.7%) had hypercholesterolemia, with 2 (1.1%) receiving cholesterol-lowering agents. We found that male sex (χ2=5.359, p=0.021), depressed or mixed state versus manic state (χ2=4.302, p=0.038), and duration of illness (t=2.756, p=0.006) were significantly associated with obesity. Older age (t=3.668, p<0.001), later age of disease onset (t=2.271, p=0.024), and lower level of educational attainment (β=-0.531, p=0.001) were associated with hyperglycemia.
Our finding that metabolic abnormalities are prevalent when initiating acute pharmacological treatment in bipolar I patients indicates that these factors should be integrated into treatment plans at the onset of disease management.
Bipolar disorder; Hypercholesterolemia; Hyperglycemia; Obesity
Longitudinal neuroimaging investigations of antidepressant treatment offer the opportunity to identify potential baseline biomarkers associated with poor outcome.
To explore the neural correlates of nonresponse to cognitive behavioural therapy (CBT) or venlafaxine (VEN), we compared pretreatment (18)F-fluoro-2-deoxy-d-glucose positron emission tomography scans of participants with major depressive disorder responding to either 16 weeks of CBT (n = 7) or VEN treatment (n = 9) with treatment nonresponders (n = 8).
Nonresponders to CBT or VEN, in contrast to responders, exhibited pretreatment hypermetabolism at the interface of the pregenual and subgenual cingulate cortices.
Limitations of our study include the small sample sizes and the absence of both arterial sampling to determine absolute glucose metabolism and high-resolution structural magnetic resonance imaging coregistration for region-of-interest analyses.
Our current findings are consistent with those reported in previous studies of relative hyperactivity in the ventral anterior cingulate cortex in treatment-resistant populations.
Symptomatic remission is the optimal outcome in depression. A brief, validated tool for symptom measurement that can indicate when remission has occurred in mental health and primary care settings is unavailable. We evaluated a 7-item abbreviated version (HAMD-7) of the 17-item Hamilton Depression Rating Scale (HAMD-17) in a randomized controlled clinical trial of patients with major depressive disorder being cared for in primary care settings.
We enrolled 454 patients across 47 primary care settings who met DSM-IV-TR criteria for a major depressive disorder. Of these, 410 patients requiring antidepressant medication were randomized to have their symptoms rated with either HAMD-7 (n = 205) or HAMD-17 (n = 205) as the primary measurement tool. The primary outcome was the proportion of patients who achieved a-priori defined responses to 8 weeks of therapy using each instrument.
Of the 205 participants per group, 67% of those evaluated with HAMD-7 were classified as having responded to therapy (defined as a ≥ 50% reduction from the pretreatment score), compared with 74% of those evaluated with HAMD-17 (p = 0.43). The difference between the groups' changes in scores from baseline (pretreatment) to endpoint was significant (p < 0.001), without a main effect of group (p = 0.84) or group-by-time (p = 0.83) interaction. The HAMD-7 test was brief to administer (e.g., 3–4 min for 85% of the primary care physicians evaluated), which facilitated the efficient and structured evaluation of salient depressive symptoms.
The abbreviated HAMD-7 depression scale is equivalent to the HAMD-17 in assessing remission in patients with a major depressive disorder undergoing drug therapy.
Contemporary mechanistic models of several psychiatric disorders propose abnormalities in the structure and function of distinct neural networks. The cerebellum has both anatomic and functional connections to the prefrontal cortex, the subcortical limbic structures and monoamine-producing brainstem nuclei. Conspicuously, however, the cerebellum has been underemphasized in neuropsychiatric research. A growing confluence of scientific data indicate that the cerebellum may not be irrelevant, which suggests that an integrated model of neuropsychiatric disorders should include a role for the cerebellum and its relevant neural connections. This review summarizes the published data describing and characterizing the putative role of the cerebellum in normal and abnormal mood regulation, with specific attention to states of psychosis, depression and mania. The available evidence suggests that a functional role for the cerebellum should be considered in future neuropsychiatric studies.
cerebellum; schizophrenia; depressive disorder, major; bipolar disorder; magnetic resonance imaging; positron-emission tomography
OBJECTIVE: To provide family physicians with a contemporary approach to formulating a treatment model for major depressive disorder that integrates definitions of new therapeutic end points, familiarizes them with tools for assessing these end points, and describes newer methods for enhancing outcome. SOURCES OF INFORMATION: Canadian Psychiatric Association Guidelines for the Treatment of Depressive Disorders, relevant articles from a MEDLINE search using the MeSH headings"full remission" and "depression," and the authors' clinical experience. MAIN MESSAGE: Major depressive disorder is an episodic, relapsing, and sometimes chronic illness. Depressive symptoms in primary care settings are often vague reports of anhedonia, anxiety, and nonspecific somatic complaints. Therapeutic objectives in depression are full remission of depressive symptoms, prevention of recurrence, and restoration of function. Depression rating scales can be useful for monitoring and treating depression. CONCLUSION: The proposed therapeutic model anticipates the chronic course of illness, defines treatment end points, encourages longer duration of treatment, and includes both pharmacologic and lifestyle therapies. The 7-item Hamilton Depression Rating Scale can assist clinicians in determining when full remission has occurred.
OBJECTIVE: To provide an evidence-based summary of medications commonly used for bipolar disorders and a practical approach to managing bipolar disorders in the office. QUALITY OF EVIDENCE: Articles from 1990 to 2003 were selected from MEDLINE using the key words "bipolar disorder," "antiepileptics," "antipsychotics," "antidepressants," and "mood stabilizers." Good-quality evidence for many of these treatments comes from randomized trials. Lithium, divalproex, carbamazepine, lamotrigine, oxcarbazepine, and some novel antipsychotics all have level I evidence for treating various aspects of the disorder. MAIN MESSAGE: Treatment of bipolar disorder involves three therapeutic domains: acute mania, acute depression, and maintenance. Lithium has been a mainstay of treatment for some time, but antiepileptic drugs like divalproex, carbamazepine, and lamotrigine, along with novel antipsychotic drugs like olanzapine, risperidone, and quetiapine, alone or in combination, are increasingly being used successfully to treat acute mania and to maintain mood stability. CONCLUSION: Bipolar disorder is more common in family practice than previously believed. Drug treatments for this complex disorder have evolved rapidly over the past decade, radically changing its management. Treatment now tends to be very successful.
OBJECTIVE: To provide family physicians with practical ways of managing depressed patients responding insufficiently to initial antidepressant treatment. QUALITY OF EVIDENCE: A search of MEDLINE and relevant bibliographies showed most studies could be categorized as level III evidence. Few well controlled studies (eg, level I evidence) specify treatment of next choice in rigorously defined treatment-refractory depression (TRD). MAIN MESSAGE: Failure to achieve and sustain full symptom remission affects relatively few treated depressed patients. Most chronically depressed people are not absolutely resistant but are relatively resistant to treatment; they fail to achieve the goals of treatment because of improper diagnosis or insufficient treatment application. The literature on TRD has largely focused on medication strategies; fewer studies investigated psychosocial approaches. The best established augmentation strategies are lithium salts and triidothyronine (T3). Combination antidepressants have become clinical psychiatrists' preferred treatment, despite limited evidence. Electroconvulsive therapy (ECT) remains a feasible option for TRD, but response rates are poor among people with TRD. High relapse rates after ECT remain a serious and common clinical dilemma. CONCLUSION: Family physicians should familiarize themselves with some new strategies to modify inadequate response to initial antidepressant treatment.
To describe the effectiveness and tolerability of reboxetine under Special Access Program conditions in Canada in a group of patients with refractory depressive disorders.
Retrospective open-label study.
Six clinical academic settings in Canada, primarily tertiary institutional settings.
Twenty-six female and 19 male outpatients with depressive disorders, primarily unipolar depression. Most of the patients were treatment resistant.
Reboxetine through the Special Access Program.
Severity of depression before treatment with reboxetine was retrospectively assessed with the Clinical Global Impression (CGI) Global Severity Scale; change with treatment was evaluated with the CGI Global Improvement Scale.
Before reboxetine treatment, 20 (44;) patients scored in the moderate CGI severity category, 11 (24%) in the marked category and 12 (27%) in the severe category. The dose range for reboxetine was 2–16 mg, with 40 (89%) patients in the 4–10 mg range. With reboxetine treatment, 25 (56%) patients were considered “very much improved” or “much improved”; 8 (18%) patients were “minimally improved”; 7 (16%) received ratings that reflected “no change” or minimal worsening, and 5 (11%) were rated as “much worse” or “very much worse.”
Reboxetine was effective at a clinically meaningful level in decreasing severity of depression in 56% of patients. Given the high rate of prior resistance to other antidepressant therapies, there is a definite role for this agent in the treatment of depressive disorders.
adrenergic uptake inhibitors; antidepressive agents; depressive disorder; treatment outcome
Full remission should be the goal of antidepressant therapy; anything less leaves the patient with residual symptoms and an increased risk of relapse and recurrence. Most antidepressant agents offer similar rates of response, but there are some differences in the ability of different agents to promote a full remission. The greatest chance of achieving full remission occurs early in the course of treatment; thus, initial antidepressant strategies should be those that have the greatest therapeutic potential. Other strategies that may help improve the chances of achieving full remission include optimizing drug dosages and using combination and augmentation strategies. Failure to achieve full remission and early discontinuation of antidepressant therapy have been associated with a greater incidence of relapse and recurrence. Continued antidepressant therapy has clearly been shown to effectively reduce the probability of relapse and recurrence by about half compared with placebo. Therefore, once a patient achieves remission, it is important to continue the same antidepressant therapy for at least 6–12 months and, for many patients, considerably longer. Medication should continue at the dose that was initially effective because using low-dose maintenance therapy appears to decrease the protective benefits.
antidepressive agents; depressive disorder; dose–response relationship, drug; drug therapy; lithium carbonate; recurrence; remission induction; treatment outcome
The 17-item Hamilton Rating Scale for Depression (HAM-D17) has been used for 4 decades as the “gold standard” instrument to assess the severity of depression and response to therapy in clinical research. The clinical utility of the HAM-D17 is hampered, in part, by the length of time required to administer the interview and by concern about a lack of inter-rater reliability. Several groups have developed shorter versions of the HAM-D17 for use in clinical practice. However, despite extensive research highlighting the importance of achieving full remission in minimizing the risk of relapse and recurrence, these shortened questionnaires have not been validated for the task of distinguishing between remission and response. A shortened form of the HAM-D17 with cut-off scores for full remission would offer a useful tool that physicians could readily employ in clinical practice. On the basis of the responses of a sample of 292 patients with major depression who received standard clinical treatment at a tertiary university affiliated hospital (Depression Clinic, Centre for Addiction and Mental Health, Toronto, Ont.) we derived a shortened versionof the HAM-D. Seven items with the greatest frequency of occurrence and sensitivity to change with treatment were identified and designated as the Toronto HAM-D7. A score of 3 or less on the Toronto HAM-D7 was found to correlate with the 17-item HAM-D definition of full remission (i.e., score of 7 or less).
antidepressive agents; behavioral symptoms; depressive disorder; drug therapy; psychiatric status rating scales; recurrence; remission induction; treatment outcome.