Quality of life in bipolar disorder: towards a dynamic understanding.

BACKGROUND: Although quality of life (QoL) is receiving increasing attention in bipolar disorder (BD) research and practice, little is known about its naturalistic trajectory. The dual aims of this study were to prospectively investigate: (a) the trajectory of QoL under guideline-driven treatment and (b) the dynamic relationship between mood symptoms and QoL. METHODS: In total, 362 patients with BD receiving guideline-driven treatment were prospectively followed at 3-month intervals for up to 5 years. Mental (Mental Component Score - MCS) and physical (Physical Component Score - PCS) QoL were measured using the self-report SF-36. Clinician-rated symptom data were recorded for mania and depression. Multilevel modelling was used to analyse MCS and PCS over time, QoL trajectories predicted by time-lagged symptoms, and symptom trajectories predicted by time-lagged QoL. RESULTS: MCS exhibited a positive trajectory, while PCS worsened over time. Investigation of temporal relationships between QoL and symptoms suggested bidirectional effects: earlier depressive symptoms were negatively associated with mental QoL, and earlier manic symptoms were negatively associated with physical QoL. Importantly, earlier MCS and PCS were both negatively associated with downstream symptoms of mania and depression. CONCLUSIONS: The present investigation illustrates real-world outcomes for QoL under guideline-driven BD treatment: improvements in mental QoL and decrements in physical QoL were observed. The data permitted investigation of dynamic interactions between QoL and symptoms, generating novel evidence for bidirectional effects and encouraging further research into this important interplay. Investigation of relevant time-varying covariates (e.g. medications) was beyond scope. Future research should investigate possible determinants of QoL and the interplay between symptoms and wellbeing/satisfaction-centric measures of QoL.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Methodological approaches to situational analysis in global mental health: a scoping review.

Global inequity in access to and availability of essential mental health services is well recognized. The mental health treatment gap is approximately 50% in all countries, with up to 90% of people in the lowest-income countries lacking access to required mental health services. Increased investment in global mental health (GMH) has increased innovation in mental health service delivery in LMICs. Situational analyses in areas where mental health services and systems are poorly developed and resourced are essential when planning for research and implementation, however, little guidance is available to inform methodological approaches to conducting these types of studies. This scoping review provides an analysis of methodological approaches to situational analysis in GMH, including an assessment of the extent to which situational analyses include equity in study designs. It is intended as a resource that identifies current gaps and areas for future development in GMH. Formative research, including situational analysis, is an essential first step in conducting robust implementation research, an essential area of study in GMH that will help to promote improved availability of, access to and reach of mental health services for people living with mental illness in low- and middle-income countries (LMICs). While strong leadership in this field exists, there remain significant opportunities for enhanced research representing different LMICs and regions.

Effects on readiness to change of an educational intervention on depressive disorders for general physicians in primary care based on a modified Prochaska model--a randomized controlled study.

BACKGROUND: The Prochaska model of readiness to change has been proposed to be used in educational interventions to improve medical care. OBJECTIVE: To evaluate the impact on readiness to change of an educational intervention on management of depressive disorders based on a modified version of the Prochaska model in comparison with a standard programme of continuing medical education (CME). METHODS: This is a randomized controlled trial within primary care practices in southern Tehran, Iran. The participants included 192 general physicians working in primary care (GPs) were recruited after random selection and randomized to intervention (96) and control (96). Intervention consisted of interactive, learner-centred educational methods in large and small group settings depending on the GPs' stages of readiness to change. Change in stage of readiness to change measured by the modified version of the Prochaska questionnaire was the RESULTS: The final number of participants was 78 (81%) in the intervention arm and 81 (84%) in the control arm. Significantly (P < 0.01), more GPs (57/96 = 59% versus 12/96 = 12%) in the intervention group changed to higher stages of readiness to change. The intervention effect was 46% points (P < 0.001) and 50% points (P < 0.001) in the large and small group setting, respectively. CONCLUSIONS: Educational formats that suit different stages of learning can support primary care doctors to reach higher stages of behavioural change in the topic of depressive disorders. Our findings have practical implications for conducting CME programmes in Iran and are possibly also applicable in other parts of the world.

Associated disturbances in calcium homeostasis and G protein-mediated cAMP signaling in bipolar I disorder.

BACKGROUND: Evidence of extensive cross-talk between calcium (Ca(2+))- and cAMP-mediated signaling systems suggests that previously reported abnormalities in Ca(2+) homeostasis in bipolar I (BP-I) patients may be linked to disturbances in the function of G proteins that mediate cAMP signaling. METHODS: To test this hypothesis, the beta-adrenergic agonist, isoproterenol, and the G protein activator, sodium fluoride (NaF), were used to stimulate cAMP production in B lymphoblasts from healthy and BP-I subjects phenotyped on basal intracellular calcium concentration ([Ca(2+)](B)). cAMP was measured by radioimmunoassay and [Ca(2+)](B) by ratiometric fluorometry with fura-2. RESULTS: Isoproterenol- (10 microM) stimulated cAMP formation was lower in intact B lymphoblasts from BP-I patients with high [Ca(2+)](B) (>/= 2 SD above the mean concentration of healthy subjects) compared with patients having normal B lymphoblast [Ca(2+)](B) and with healthy subjects. Although basal and NaF-stimulated cAMP production was greater in B lymphoblast membranes from male BP-I patients with high versus normal [Ca(2+)](B), there were no differences in the percent stimulation. This suggests the differences in NaF response resulted from higher basal adenylyl cyclase activity. CONCLUSIONS: These findings suggest that trait-dependent disturbances in processes regulating beta-adrenergic receptor sensitivity and G protein-mediated cAMP signaling occur in conjunction with altered Ca(2+) homeostasis in those BP-I patients with high B lymphoblast [Ca(2+)](B).

Altered TRPC7 gene expression in bipolar-I disorder.

BACKGROUND: As altered storage-operated calcium (Ca(2+)) entry (SOCE) may affect Ca(2+) homeostasis in bipolar disorder (BD), we determined whether changes occur in the expression of TRPC7 and SERCA2s, proteins implicated or known to be involved in SOCE, in B lymphoblast cell lines (BLCLs) from BD-I patients and comparison subjects. METHODS: mRNA levels were determined in BLCL lysates from BD-I, BD-II, and major depressive disorder patients, and healthy subjects by comparative reverse transcriptase-polymerase chain reaction, and BLCL basal intracellular Ca(2+) concentration ([Ca(2+)]B) was determined by ratiometric spectrophotometry using Fura-2, in aliquots of the same cell lines, at 13-16 passages in culture. RESULTS: TRPC7 mRNA levels were significantly lower in BLCLs from BD-I patients with high BLCL [Ca(2+)]B compared with those showing normal [Ca(2+)]B (-33%, p =.017) and with BD-II patients (-48%, p =.003), major depressive disorder patients (-47%, p =.049) and healthy subjects (-33%, p =.038). [Ca(2+)]B also correlated inversely with TRPC7 mRNA levels in BLCLs from the BD-I group as a whole (r = -.35, p =.027). CONCLUSIONS: Reduced TRPC7 gene expression may be a trait associated with pathophysiological disturbances of Ca(2+) homeostasis in a subgroup of BD-I patients.

Reversed neurovegetative symptoms of depression: a community study of Ontario.

OBJECTIVE: Most research on depression with reversed neurovegetative features (hypersomnia, hyperphagia, and weight gain) has been based on site-specific clinic-based samples. The goal of this study was to delineate the epidemiology of reversed symptoms in a large community sample and to use other symptom patterns for comparison. METHOD: Interviewers assessed 8,116 subjects across Ontario, aged 15-64 years, by using the World Health Organization Composite International Diagnostic Interview. Individuals who met the DSM-III-R criteria for major depression, current or lifetime, were classified into four groups on the basis of lifetime neurovegetative symptoms: episodes of typical symptoms only, episodes of reversed symptoms only, neither type, or both types (fluctuating-symptom group). The groups were compared on demographic characteristics, comorbidity, disability, and health care utilization. RESULTS: Of the 653 individuals with lifetime major depression, 11.3% had episodes of reversed symptoms only, and another 5.8% were classified as fluctuating. Most of the differences among the four groups were due to the unique characteristics of the groups with neither type of episode or a fluctuating pattern; individuals who had experienced only reversed symptoms were remarkably similar to those who had had only typical symptoms. The fluctuating-symptom group had high rates of comorbidity, substance abuse, and health care utilization. CONCLUSIONS: Several popular beliefs about depression with reversed features did not hold true for this community sample. Identifying individuals who fluctuate between reversed and typical episodes may be important in studies of major depression, in particular when reversed neurovegetative symptoms are a consideration.

Use of antidepressants among elderly subjects: trends and contributing factors.

OBJECTIVE: The authors assessed changes over time in antidepressant utilization among elderly subjects regarding the prevalence of antidepressant users, shifts in prescription patterns, and related financial implications. METHOD: The authors conducted a population-based study of more than 1.4 million Ontario residents aged 65 years or older. Cross-sectional data regarding annual antidepressant utilization were obtained from administrative databases for 1993 to 1997. Time series analysis was used to assess trends over time and to make future projections. RESULTS: The proportion of antidepressant users increased from 9.3% of the elderly population in 1993 to 11.5% in 1997. Prescriptions for selective serotonin reuptake inhibitors (SSRIs) accounted for 9.6% of antidepressant prescriptions dispensed in the first 30 days of 1993 and 45.1% of those dispensed by the last 30 days of 1997 and were projected to increase to approximately 56% by the end of 2000. Prescriptions for tricyclic antidepressants fell from 79.0% in the first 30 days of 1993 to 43.1% by the last 30 days of 1997 and were projected to decline to approximately 28% by the end of 2000. Annual antidepressant costs (in Canadian dollars) increased by 150%, from $10.8 million in 1993 to $27.0 million in 1997. Population shifts and an increase in the prevalence of antidepressant users accounted for at least 20% of this increase, whereas the prescribing transition from tricyclic antidepressants to SSRIs accounted for at least 61% of the increase. CONCLUSIONS: The introduction of SSRIs has had a substantial financial impact at the drug utilization level. Future research should address the appropriate balancing of the cost of newer agents versus their ostensible advantages.

Genetic association analysis of serotonin system genes in bipolar affective disorder.

OBJECTIVE: This study examined the putative role of serotonin genes in the etiology of bipolar affective disorder. METHOD: Genetic association analysis was performed for individuals with bipolar affective disorder and unaffected subjects closely matched in age, sex, and ethnic background (N=103 in each group). The allele and genotype frequencies of polymorphisms at the genes for serotonin receptors HTR1A, HTR1Dalpha, HTR1Dbeta, HTR2A, HTR2C, HTR7, tryptophan hydroxylase (TPH), and the serotonin transporter (hSERT) were compared in the two groups of subjects. RESULTS: Statistically significant positive associations were found for HTR2A and hSERT polymorphisms. However, results from an independent replication group of over 100 patients with bipolar affective disorder and their matched comparison subjects failed to confirm these associations. CONCLUSIONS: These results suggest that the serotonin genes studied are not associated with bipolar affective disorder, although transmission disequilibrium studies are required in order to confirm this conclusion.

Major depression in individuals with a history of childhood physical or sexual abuse: relationship to neurovegetative features, mania, and gender.

OBJECTIVE: Numerous studies have linked childhood trauma with depressive symptoms over the life span. However, it is not known whether particular neurovegetative symptom clusters or affective disorders are more closely linked with early abuse than are others. In a large community sample from Ontario, the authors examined whether a history of physical or sexual abuse in childhood was associated with particular neurovegetative symptom clusters of depression, with mania, or with both. METHOD: The World Health Organization Composite International Diagnostic Interview was used to assess 8,116 individuals aged 15-64 years. Each subject was asked about early physical and sexual abuse experiences on a structured supplement to the interview. Six hundred fifty-three cases of major depression were identified. Rates of physical and sexual abuse in depressive subgroups defined by typical and reversed neurovegetative symptom clusters (i.e., decreased appetite, weight loss, and insomnia versus increased appetite, weight gain, and hypersomnia, respectively) and by the presence or absence of lifetime mania were compared by gender. RESULTS: A history of physical or sexual abuse in childhood was associated with major depression with reversed neurovegetative features, whether or not manic subjects were included in the analysis. A strong relationship between mania and childhood physical abuse was found. Across analyses there was a significant main effect of female gender on risk of early sexual abuse; however, none of the group-by-gender interactions predicted early abuse. CONCLUSIONS: These results suggest an association between early traumatic experiences and particular symptom clusters of depression, mania, or both in adults.

The 5HT1Dbeta receptor gene in bipolar disorder: a family-based association study.

The serotonin (5HT) receptor genes are considered good candidates for Major Depression (MD), Bipolar Disorder (BP), and Obsessive-Compulsive Disorder (OCD). The 5HT1Dbeta receptor gene has at least three polymorphisms known: G861C, T-261G, and the functional T371G (Phe-124-Cys). The aim of this study was to investigate for the presence of linkage disequilibrium between the 5HT1Dbeta receptor gene and BP. Two hundred and ninety probands with DSM-IV BPI, BPII, or Schizoaffective Disorder (Bipolar type) with their living parents were recruited. Genotyping data for the G861C and T371G polymorphisms were analyzed using the Transmission Disequilibrium Test (TDT). One hundred and sixty triads were informative for the TDT on the G861C polymorphism, which showed no preferential transmission of either allele (chi-square = 0.438, df = 1, p =.508). Only four triads were suitable for the analysis on the T371G variant, with the T allele transmitted once and the G allele transmitted four times to the affected. These findings validate further the results of pharmacological studies excluding a direct involvement of the 5HT1Dbeta receptor in the pathogenesis of BP. Further investigations combining genetic and pharmacological strategies are warranted.

Sociodemographic, clinical, and attitudinal characteristics of the untreated depressed in Ontario.

BACKGROUND: Epidemiologic surveys consistently document high rates of untreated depression, yet why this unmet need exists is only partially understood. METHODS: We compared untreated depressed, treated depressed and "healthy" subjects on sociodemographic characteristics, need for treatment, and help-seeking attitudes using household survey data from Ontario, Canada (n = 9953). DSM-III R Major Depression was assessed by structured interview (UM-CIDI), and treatment was defined as seeking formal mental health care. Need for treatment was assessed using a broad array of clinical, disability, and risk measures. RESULTS: Depressed (treated and untreated) and "healthy" respondents differed significantly on nearly all comparative measures. However, the two depressed groups showed few sociodemographic or "need for treatment" differences. Notably, there were no significant clinical differences although the untreated did report less physical comorbidity (33.9% vs 60.0% treated depressed). There were, however, several attitudinal differences. Compared to the treated depressed, untreated respondents were less likely to feel they had a mental health problem (51.6% vs. 78.8%), to say they would seek help for a serious problem (36.6% vs 64.7%) or to feel comfortable consulting a professional (19.0% vs. 43.2%). LIMITATIONS: Because the data are cross-sectional, temporal relationships cannot be directly addressed. CONCLUSIONS: Despite appreciable morbidity, access to care by the untreated depressed may be hindered by their self-perceptions and greater discomfort with help-seeking. Lower physical comorbidity may also contribute through decreased health care contact and thus fewer opportunities for disclosing or detecting their illness.

Clinical characteristics of bipolar disorder subjects with large CAG/CTG repeat DNA.

BACKGROUND: Unstable DNA has been implicated in a variety of neuropsychiatric disorders, with increasing severity of disease associated with larger DNA repeats. We examined the unstable DNA hypothesis for bipolar disorder by looking for increased severity of symptoms and earlier age of onset amongst bipolar individuals with large CAG/CTG repeats. METHODS: From a sample of 91 bipolar subjects, eight with large CAG/CTG (> or = 270bp) trinucleotide repeats were matched to eight bipolar individuals with small repeats (< or = 150bp). Medical charts were reviewed for age of onset and a number of severity indicators. Candidate CAG/CTG expansions on chromosomes 17 and 18 were also genotyped. RESULTS: No obvious differences were noted for the clinical indices, however seven out of eight individuals with large Repeat Expansion Detection (RED) products had expansions at the CTG18.1 locus, while four out of eight had large repeats at ERDA1. Both of these sites are unlikely to be related to disease. LIMITATIONS: Our total sample size is small and less than 9% have large repeats. CONCLUSIONS: The lack of increased severity or earlier age of onset amongst bipolar subjects with large CAG/CTG repeats suggests these repeats are unlikely to have a major etiological role in bipolar disorder.

Mood disorders: rural/urban differences in prevalence, health care utilization, and disability in Ontario.

This study examines whether rural Ontario differs from urban Ontario in mood disorder prevalence, health service use and concomitant disability. An epidemiologic community survey of 9953 individuals was conducted, with rural/urban status defined by population-density-related criteria. Overall, Ontario prevalence rates for depression, manic episode, and dysthymia were similar to previous studies, but rural rates were unexpectedly no different from urban ones. Nearly half of mood disorder subjects used no services, and one-third reported significant disability. Rural individuals with mood disorders were similar to their urban counterparts in service use and disability.

Depression in Ontario: under-treatment and factors related to antidepressant use.

Our study examines how depression is treated in Ontario, with particular examination of the correlates of antidepressant utilization using a broad model of individual (clinical), demographic, and health system determinants of treatment. From a community epidemiologic survey, a sample of 333 individuals with major depression in the past year was identified. More than half received no treatment (untreated n = 170, 51.1%), while 74 (22.2%) received treatment without medication, 29 (8.7%) received treatment mainly with anxiolytics, and only 60 (18.0%) were treated with antidepressants. All four groups had similar rates of alcohol and substance abuse. Disability and comorbid anxiety were common, with the least in the untreated group and the most in the antidepressant group. Increased use of antidepressants was associated with psychiatrist contact, while family physicians treated a substantial minority primarily with anxiolytics. Under a universal health care system, no differential access to antidepressants was found in terms of demographic characteristics. Clinical severity and contact with a psychiatrist correlate with antidepressant treatment of depression.

Effectiveness of psychosocial treatments in bipolar disorder: state of the evidence.

Cost-effective psychotherapeutic interventions can enhance pharmacotherapy and improve outcomes in major depression and schizophrenia, but they are rarely studied in bipolar disorder, despite its often unsatisfactory response to medication alone. Following a literature search, we compiled and evaluated research reports on psychotherapeutic interventions in bipolar disorder patients. We found 32 peer-reviewed reports involving 1052 patients-14 studies on group therapy, 13 on couples or family therapy, and five on individual psychotherapy-all supplementing standard pharmacotherapy. Methodological limitations were common in these investigations. Nevertheless, important gains were often seen, as determined by objective measures of increased clinical stability and reduced rehospitalization, as well as other functional and psychosocial benefits. The results should further encourage rising international interest in testing the clinical and cost-effectiveness of psychosocial interventions in these common, often severe and disabling disorders.

Applying Prochaska's model of change to needs assessment, programme planning and outcome measurement.

A major goal of continuing medical education (CME) is to enhance the performance of the learner. In order to accomplish this goal, careful consideration and expertise must be applied to the three primary ingredients of CME planning: assessing learner needs, programme design and outcome measurement. Traditional methods used to address these three components seldom result in CME initiatives that change performance, even in the presence of sophisticated CME formats and capable learners. In part, performance may not change because the learner is not 'ready to change'. Planners of CME are aware of this concept but have been unable to measure 'readiness to change' or employ it in assessing learner needs, and planning and evaluating CME. One theory that focuses on an individual's readiness to change is Prochaska's model, which postulates that change is a gradual process proceeding through specific stages, each of which has key characteristics. This paper examines the applicability of this model to all components of CME planning. To illustrate the importance of this model, this paper provides examples of these three components conducted both with and without implementation of this model.

Clinical guidelines for the treatment of depressive disorders, I. Definitions, prevalence, and health burden.

BACKGROUND: The Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments partnered to produce clinical guidelines for psychiatrists for the treatment of depressive disorders. METHODS: A standard guidelines development process was followed. Relevant literature was identified using a computerized Medline search supplemented by review of bibliographies. Operational criteria were used to rate the quality of scientific evidence, and the line of treatment recommendations included consensus clinical opinion. This section on "Definitions, Prevalence, and Health Burden" was 1 of 7 articles drafted and reviewed by clinicians. Revised drafts underwent national and international expert peer review. RESULTS: The 1-year prevalence rate of major depressive disorder (MDD) in Canada is 3.2% to 4.6%, similar to the rates in other countries. MDD frequently runs a chronic or recurrent course and carries high risks for mortality and morbidity. The significant economic costs and disability associated with depressive illness are reduced by effective treatment. CONCLUSIONS: MDD is a prevalent medical condition that results in a significant health burden in the world. Vigorous efforts to improve diagnosis, treatment, and prevention are indicated to reduce the societal and personal costs of depressive disorders.

Mental health treatment in Ontario: selected comparisons between the primary care and specialty sectors.

OBJECTIVE: Epidemiologic research has demonstrated that the majority of mental illness in the community is not treated. Primary care physicians and the specialty mental health sector each have an important role in the provision of mental health services. Our goal is to clarify the extent of undertreatment of selected mental illnesses in Ontario and to examine how treatment is divided between the primary care and specialty sectors. In particular, we are interested in both the relative numbers and the types--based on sociodemographic and severity indicators--of patients found in each sector, as well as in confirming the key role of primary care in the provision of mental health services. METHODS: Data were taken from the Mental Health Supplement to the Ontario Health Survey, a community survey of 9953 individuals. All subjects who met DSM-III-R criteria for a past year diagnosis of mood, anxiety, substance abuse, bulimic, or antisocial personality disorders were categorized by their use of mental health services in the preceding year--into nonusers, primary care only patients, specialty only patients, and both sector patients. The 3 groups utilizing services were then compared by demographic, clinical, and disability characteristics. RESULTS: Only 20.8% of subjects with a psychiatric diagnosis reported use of mental health services, but 82.9% of these same individuals used primary care physicians for general health problems. Among those who used mental health services, 38.2% used family physicians only for psychiatric treatment, compared with 35.8% who used only specialty mental health providers, and 26.0% who used both sectors. The 3 groups of users showed only modest differences on sociodemographic characteristics. Patients in the specialty only sector reported significantly higher rates of sexual and physical abuse. On specific disability measures, all 3 groups were similar. CONCLUSION: The vast majority of individuals with an untreated psychiatric disorder are using the primary care sector for general health treatment, allowing an opportunity for identification and intervention. Primary care physicians also treat the majority of those seeking mental health services, and individuals seen only by these primary care physicians are probably as ill as those seen exclusively in the specialty mental health sector. From a public health perspective, future policy interventions should aim to improve collaboration between the 2 sectors and enhance the ability of primary care physicians to deliver psychiatric services.