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Is bipolar disorder still underdiagnosed? Are antidepressants overutilized?
Abstract
Previous studies have suggested that bipolar disorder may be underdiagnosed, and that antidepressants may be over-utilized in its treatment.
Consecutively admitted patients (n =48) diagnosed with DSM-IV bipolar disorder, type I, (n = 44) or schizoaffective disorder, bipolar type, (n = 4) were interviewed systematically and their charts were reviewed to confirm diagnosis before admission. They were then treated according to systematic structured interview diagnoses. These data reflect the changes in diagnoses and treatment.
40% (19/48) were identified with previously undiagnosed bipolar disorder, all previously diagnosed with unipolar major depressive disorder. A period of 7.5+/-9.8 years elapsed in this group before bipolar diagnosis was made. Antidepressant use was high on admission (38%) and was reduced with acceptable treatment response rates. The adjunctive use of risperidone appeared to be a good treatment alternative.
While diagnoses were made prospectively, treatment response was assessed retrospectively, and was based on non-randomized, naturalistic therapy.
Systematic application of DSM-IV criteria identified previously undiagnosed bipolar disorder in 40% of a referred population of patients with mood disorders, all previously misdiagnosed as unipolar major depressive disorder. Antidepressants appeared overutilized and risperidone was an effective alternative adjunctive therapy agent.
... The onset of bipolar disorder in a majority of cases is characterized by depressive episodes rather than mania or hypomania, with 58-71% of bipolar I cases and over 90% of bipolar II cases initially presenting with depression (Etain et al. 2012; ). Consequently, between 37% and 69% of those eventually diagnosed with bipolar disorder were initially diagnosed with major depressive disorder (MDD) [Ghaemi et al. 2000;Ghaemi et al. 1999;Hirschfeld et al. 2003]. There is typically a delay of about 4 to 9 years from the rst psychiatric consultation or provisional MDD diagnosis to a con rmed bipolar disorder diagnosis [Ghaemi et al. 2000; Ghaemi et al. 1999; Watanabe et al. 2016; Inoue et al. 2015]. ...
... Consequently, between 37% and 69% of those eventually diagnosed with bipolar disorder were initially diagnosed with major depressive disorder (MDD) [Ghaemi et al. 2000;Ghaemi et al. 1999;Hirschfeld et al. 2003]. There is typically a delay of about 4 to 9 years from the rst psychiatric consultation or provisional MDD diagnosis to a con rmed bipolar disorder diagnosis [Ghaemi et al. 2000; Ghaemi et al. 1999; Watanabe et al. 2016; Inoue et al. 2015]. The rate at which diagnoses change from MDD to bipolar disorder varies signi cantly, ranging from 2% over 21 years to 20% within 3 years [Mattisson et al. 2007; Akiskal et al. 1983; Kessing et al. 2017]. ...
Background
Bipolar disorder often emerges from depressive episodes and is initially diagnosed as depression. This study aimed to explore the effects of a prior depression diagnosis on outcomes in patients diagnosed with bipolar disorder.
Methods
This cohort study analyzed data of patients aged 18–64 years who received a new bipolar disorder diagnosis in Japan, using medical claims data from January 2005 to October 2020 provided by JMDC, Inc. The index month was defined as the time of the bipolar diagnosis. The study assessed the incidence of psychiatric hospitalization, all-cause hospitalization, and mortality, stratified by the presence of a preceding depression diagnosis and its duration (≥ 1 or < 1 year). Hazard ratios (HRs) and p-values were estimated using Cox proportional hazards models, adjusted for potential confounders, and supported by log-rank tests.
Results
Of the 5,595 patients analyzed, 2,460 had a history of depression, with 1,049 experiencing it for over a year and 1,411 for less than a year. HRs for psychiatric hospitalization, all hospitalizations, and death in patients with a history of depression versus those without were 0.92 (95% CI = 0.78–1.08, p = 0.30), 0.87 (95% CI = 0.78–0.98, p = 0.017), and 0.61 (95% CI = 0.33–1.12, p = 0.11), respectively. In patients with preceding depression ≥ 1 year versus < 1 year, HRs were 0.89 (95% CI = 0.67–1.19, p = 0.43) for psychiatric hospitalization, 0.85 (95% CI = 0.71-1.00, p = 0.052) for all hospitalizations, and 0.25 (95% CI = 0.07–0.89, p = 0.03) for death.
Conclusion
A prior history and duration of depression may not elevate psychiatric hospitalization risk after bipolar disorder diagnosis, and might even correlate with reduced hospitalization and mortality rates.
... They also tend to show cases of comorbidity, with other psychiatric disorders or with physical diseases, more frequently than patients with Major Depressive Disorder (MDD) (3). Furthermore, the most frequent misdiagnosis in BD is with MDD (4,5). for Bipolar II Disorder (BD II) (4,5,6). ...
... Furthermore, the most frequent misdiagnosis in BD is with MDD (4,5). for Bipolar II Disorder (BD II) (4,5,6). In Argentina, in a study developed in a clinic population, the average time for diagnosis was of 8 years for most of the patients surveyed (5). ...
Abstract
Background: Scientific literature has well established that Bipolar Disorder (BD) is frequently under-diagnosed. Studies have reported a ten-year breach between disorder onset and its proper diagnosis, in a large proportion of BD patients. However, many authors highlight the bipolar spectrum disorders over-diagnosis in patients with personality disorders, particularly cluster B. The present study compares the efficiency of several BD screening and assessment instruments to detect BD in a sample of clinical outpatients. Methods: The study included patients aged 18 to 65 years who gave written informed consent. They had to meet DSMIV R diagnostic criteria for a Mood Disorder and/or cluster B Personality Disorder. A sample of outpatients (n = 81) were assessed and arranged in 4 diagnostic groups: Major Depression (MD n=24), Bipolar Disorder (BD n=18), Cluster B Personality Disorders (PD-B n=19) and comorbidity of BD and PD-B (n=20). Patients who entered the study completed the Mood Disorder Questionnaire –MDQ, and Bipolar Spectrum Diagnostic Scale -BSDS at the time of inclusion, and patient´s therapists completed the Bipolar Index -BI and Ghaemi´s Bipolar Spectrum Criteria. The DSM-IV R diagnoses were evaluated with two semi-structured interviews (MINI and SCID-II) for axis I and axis II disorders respectively, rated by a psychiatrist or psychologist blind to the results of the screening questionnaires. The instruments were compared by their Sensitivity, Specificity, Positive and Negative Predictive Values and Positive and Negative linkhood ratio. Results show good sensitivity and specificity values for the MDQ and BSCS (specificity: 0.79 vs 0.77; sensitivity 0.74 vs 0.71 respectively) and similar positive predictive values (PPV: 73%) for both instruments to identify BD. The Bipolarity Index, with an ad hoc 50-cutoff point, revealed excellent sensitivity and specificity values (0.84 and 0.90) with PPV of 87%. Finally, the simultaneous implementation of both, the screening instruments (MDQ or BSDS) and Diagnostic Criteria of Bipolar Spectrum provided a notorious improvement in sensitivity detection whit some decline in specificity values and slightly decline in PPV, but also expanded the bipolar spectrum detection regardless of identifying manic symptoms. Conclusions: The concurrent utilization of MDQ and the Criterions Ghaemi’s Bipolar Spectrum notably increased the sensitivity for detection of BD while still maintaining reliability. The development of a questionnaire that includes screening for manic symptoms (MDQ) plus symptomatic and evolutionary characteristic of the bipolar spectrum could significantly increase the sensitivity of the screening for BD. A discussion explores the implications of the previous findings.
... In the late 1990's, similar research began to emerge about bipolar disorders (BD). The studies evaluated the latency between the age at onset (AAO) and age at diagnosis of BD and/or between the onset of BD and initiation of guideline recommended BD-specific treatment (i.e., a mood stabilizer), although findings were often reported in terms of the proportion of survey responders who experienced prolonged latencies (4)(5)(6)(7)(8)(9)(10). For example, a survey of the members of a patient advocacy organisation estimated that about 30% of individuals with a self-reported diagnosis of BD experienced a 10-year delay between the onset of symptoms and receipt of BD-specific treatments (5). ...
... For example, a survey of the members of a patient advocacy organisation estimated that about 30% of individuals with a self-reported diagnosis of BD experienced a 10-year delay between the onset of symptoms and receipt of BD-specific treatments (5). However, many of the early studies were small scale, and/or failed to provide definitions of the latency constructs, and/or reported wide-ranging estimates of delays that were difficult to interpret (6)(7)(8)(9)(10). Overall, the research was undermined by the lack of agreement about how to best translate the DUI/DUP concepts into reliable and valid markers of the early course of BD (11,12). ...
Objectives:
To examine the time delay between the age at onset of symptoms or episodes of bipolar disorders (BD) and the age at diagnosis of and/or receipt of clinical practice guideline recommended interventions for BD.
Methods:
Systematic search of five databases to identify publications from January 2000 to July 2022 that reported one or more of the following reliable and valid estimates of latency: delay in help seeking (DHS), delay in diagnosis (DD) and duration of untreated BD (DUB). Eligible studies were included in random effects meta-analyses and multivariate meta-regression was used to assess factors associated with each latency construct.
Results:
Screening of 1074 publications identified 59 eligible studies (reported in 66 publications) of >40,000 individuals that estimated DHS (8 studies), DD (20 studies) and/or DUB (45 studies). The median DHS, DD and DUB were 3.5 (IQR: 2.8, 8.48), 6.7 (IQR: 5.6, 8.9) and 5.9 years (IQR: 1.1, 8.2) respectively. Key factors associated with shorter DD included older age and residing outside North America; shorter DUB was associated with psychotic or manic onset and access to early intervention services.
Conclusions:
Greater consensus on definitions of latency constructs and better-quality targeted research is required regarding DHS, DD and DUB. This review suggests that, whilst the peak age at onset of BD is 15-25, diagnosis and guideline recommended interventions (e.g., mood stabilizers) are likely to be delayed until age 25-35 years except for a minority of individuals with access to early intervention services. This article is protected by copyright. All rights reserved.
... Approximately one-third of individuals initially diagnosed with MDD experience subsequent changes in their psychiatric diagnoses [4,5]. A significant proportion of these patients undergo diagnostic conversion to BD, and 20−60% of patients receiving treatment for BD were previously diagnosed with MDD [6,7]. Misdiagnoses and delays in diagnosis and treatment contribute to increased morbidity and mortality, poor treatment outcomes, and progression to chronic illness and neurodegeneration [8][9][10][11]. ...
... All these factors contribute to the complexity and difficulty of diagnosing bipolar disorder. Several studies have shown that the average delay to obtain an accurate diagnosis of BD is close to 10 years (Baethge et al., 2003;Fritz et al., 2017;Ghaemi et al., 1999), resulting in an inadequate treatment for almost a decade that often promotes to addictions and comorbidities development (Bauer et al., 2018). ...
Bipolar disorder (BD) is a leading cause of disability worldwide, as it can lead to cognitive and functional impairment and premature mortality. The first episode of BD is usually a depressive episode and is often misdiagnosed as major depressive disorder (MDD). Growing evidence indicates that peripheral immune activation and inflammation are involved in the pathophysiology of BD and MDD. Recently, by developing a panel of RNA editing-based blood biomarkers able to discriminate MDD from depressive BD, we have provided clinicians a new tool to reduce the misdiagnosis delay observed in patients suffering from BD. The present study aimed at validating the diagnostic value of this panel in an external independent multicentric Switzerland-based cohort of 143 patients suffering from moderate to major depression. The RNA-editing based blood biomarker (BMK) algorithm developped allowed to accurately discriminate MDD from depressive BD in an external cohort, with high accuracy, sensitivity and specificity values (82.5 %, 86.4 % and 80.8 %, respectively). These findings further confirm the important role of RNA editing in the physiopathology of mental disorders and emphasize the possible clinical usefulness of the biomarker panel for optimization treatment delay in patients suffering from BD.
... When employing the DSM-IV Clinical Interview Checklist, 24% of individuals fell within the bipolar spectrum, underscoring the importance of screening for bipolar-related symptoms in this population (Gold et al., 2018;Hasin et al., 2005). Additionally, we explored diverse definitions of bipolarity, yielding prevalence rates ranging from 6.1% for bipolar depression (Ghaemi et al., 2002) to 29.9% for the broader bipolar spectrum (Ghaemi et al., 1999). Ghaemi's conceptualization of bipolar disorders involves a more comprehensive spectrum that incorporates a wider range of mood-related experiences. ...
... A number of cases of pseudodementia in patients with bipolar disorder (BD) have been reported in the literature. It is likely that pseudodementia in the context of BD was overlooked due to the underdiagnosis of BD, particularly BD type 2. As a matter of fact, up to 40% of patients with mood disorders initially received an incorrect diagnosis of unipolar depressive disorder; these patients were later more appropriately classified as having BD [17,18]. In particular, BD seems to be underdiagnosed in old age. ...
Even though pseudodementia has been historically linked to depression, other psychiatric conditions may cause reversible cognitive alterations. The purpose of this study is to improve our understanding of pseudodementia occurring throughout the entire bipolar spectrum. A systematic review was conducted according to PRISMA guidelines. PubMed, Scopus, and Web of Science databases were searched up to March 2023. Fifteen articles on patients with pseudodementia and bipolar disorder (BD), mania, hypomania, or mixed depression have been included. Moreover, seven female patients with mood disorders diagnosed with pseudodementia have been described. According to our research, pseudodementia in patients with BD mostly occurs during a depressive episode. However, pseudodementia has also been observed in the context of manic and mixed states. Psychomotor and psychotic symptoms were commonly associated. The most typical cogni-tive impairments were disorientation, inattention, and short-term memory deficits. Alterations in neuroimaging were frequently observed. Electroconvulsive therapy and lithium, either alone or in combination with antipsychotics, resulted in the most widely used therapies. Cognitive decline may occur in a substantial proportion of patients. Since pseudodementia can manifest along the entire mood spectrum, it should be taken into consideration as a possible diagnosis in BD patients showing cognitive deficits during manic, mixed, and depressive states.
... Another factor that may delay the diagnosis is an underdiagnosis of certain mental illnesses, such as bipolar disorder, attention deficit hyperactivity disorder (ADHD), or post-traumatic stress disorder, particularly in adolescents 26,27 . Therefore, a better liaison between child and adolescent mental health services and addiction units would be required, particularly considering that DD in-dividuals start using substances at a younger age and show a much more severe and overall worse outcome 27,28 . ...
Comorbid substance use disorder (SUD) in patients with schizophrenia (dual disorder, DD) is a frequent occurrence in the psychiatric clinical practice and is positively associated with poorer outcomes. Despite a very high co-prevalence, clinical guidelines for SUD and severe mental illnesses tend to give limited consideration to co-existing disorders regarding diagnosis and management. This article is the result of a meeting held in February 2023 to discuss common challenges and best clinical practice initiatives for patients with schizophrenia and DD in different treatment settings. The authors identified issues in the clinical approach to DD in schizophrenia spectrum disorders and suggested the most suitable management based on their experience as a group of experts, identifying possible improvement areas. In conclusion, the panel recommends that individuals with DD should be cared for in a single center. Pharmacologic treatment in individuals with DD needing both control of symptoms related to schizophrenia spectrum disorders and substance withdrawal should ideally be based on using a non-sedative antipsychotic with anti-craving activity.
... A major depressive disorder or psychotic disorder diagnosis constitutes an exclusion criterion for BD according to DSM-5 [2]. However, around 40% of people who are diagnosed with BD first received a major depressive disorder diagnosis [58,59]. Therefore, only users who also reported a psychotic disorder diagnosis were removed. ...
Background
Mental health (MH) peer online forums offer robust support where internet access is common, but healthcare is not, e.g., in countries with under-resourced MH support, rural areas, and during pandemics. Despite their widespread use, little is known about who posts in such forums, and in what mood states. The discussion platform Reddit is ideally suited to study this as it hosts forums (subreddits) for MH and non-MH topics. In bipolar disorder (BD), where extreme mood states are core defining features, mood influences are particularly relevant.
Objectives
This exploratory study investigated posting patterns of Reddit users with a self-reported BD diagnosis and the associations between posting and emotions, specifically: 1) What proportion of the identified users posts in MH versus non-MH subreddits? 2) What differences exist in the emotions that they express in MH or non-MH subreddit posts? 3) How does mood differ between those users who post in MH subreddits compared to those who only post in non-MH subreddits?
Methods
Reddit users were automatically identified via self-reported BD diagnosis statements and all their 2005–2019 posts were downloaded. First, the percentages of users who posted only in MH (non-MH) subreddits were calculated. Second, affective vocabulary use was compared in MH versus non-MH subreddits by measuring the frequency of words associated with positive emotions, anxiety, sadness, anger, and first-person singular pronouns via the LIWC text analysis tool. Third, a logistic regression distinguished users who did versus did not post in MH subreddits, using the same LIWC variables (measured from users’ non-MH subreddit posts) as predictors, controlling for age, gender, active days, and mean posts/day.
Results
1) Two thirds of the identified 19,685 users with a self-reported BD diagnosis posted in both MH and non-MH subreddits. 2) Users who posted in both MH and non-MH subreddits exhibited less positive emotion but more anxiety and sadness and used more first-person singular pronouns in their MH subreddit posts. 3) Feminine gender, higher positive emotion, anxiety, and sadness were significantly associated with posting in MH subreddits.
Conclusions
Many Reddit users who disclose a BD diagnosis use a single account to discuss MH and other concerns. Future work should determine whether users exhibit more anxiety and sadness in their MH subreddit posts because they more readily post in MH subreddits when experiencing lower mood or because they feel more able to express negative emotions in these spaces. MH forums may reflect the views of people who experience more extreme mood (outside of MH subreddits) compared to people who do not post in MH subreddits. These findings can be useful for MH professionals to discuss online forums with their clients. For example, they may caution them that forums may underrepresent people living well with BD.
... The overlapping depressive symptoms in BD and MDD pose a great challenge to the realization of rapid and accurate clinical diagnosis (Belmaker and Agam, 2008;Hirschfeld, 2014) (Figure 1B). It is estimated that about 50-75% of BD patients were initially misdiagnosed as MDD (Hirschfeld et al., 2003;Tondo et al., 2014), with an average misdiagnosis time of 10 years, even longer for young BD (Godwin and Jam, 2008), resulting in about one-third of BD patients not receiving appropriate treatment (Ghaemi et al., 1999). Antidepressants are the first-line treatment for depressive episodes, but in patients with bipolar depression, antidepressants carry a significant risk of inducing manic episodes or hypomanic episodes and may also increase the risk of suicidal behavior and cause adverse consequences of chronicity in the course of BD, especially among adolescents (Faedda et al., 2004;Akiskal and Benazzi, 2005;Baldessarini et al., 2005;Perlis et al., 2011), all of which may lead to a poorer ultimate clinical and functional prognosis and further burden the individual, family, and society. ...
Background
Mood disorders are very common among adolescents and include mainly bipolar disorder (BD) and major depressive disorder (MDD), with overlapping depressive symptoms that pose a significant challenge to realizing a rapid and accurate differential diagnosis in clinical practice. Misdiagnosis of BD as MDD can lead to inappropriate treatment and detrimental outcomes, including a poorer ultimate clinical and functional prognosis and even an increased risk of suicide. Therefore, it is of great significance for clinical management to identify clinical symptoms or features and biological markers that can accurately distinguish BD from MDD. With the aid of bibliometric analysis, we explore, visualize, and conclude the important directions of differential diagnostic studies of BD and MDD in adolescents.
Materials and methods
A literature search was performed for studies on differential diagnostic studies of BD and MDD among adolescents in the Web of Science Core Collection database. All studies considered for this article were published between 2004 and 2023. Bibliometric analysis and visualization were performed using the VOSviewer and CiteSpace software.
Results
In total, 148 publications were retrieved. The number of publications on differential diagnostic studies of BD and MDD among adolescents has been generally increasing since 2012, with the United States being an emerging hub with a growing influence in the field. Boris Birmaher is the top author in terms of the number of publications, and the Journal of Affective Disorders is the most published journal in the field. Co-occurrence analysis of keywords showed that clinical characteristics, genetic factors, and neuroimaging are current research hotspots. Ultimately, we comprehensively sorted out the current state of research in this area and proposed possible research directions in future.
Conclusion
This is the first-ever study of bibliometric and visual analyses of differential diagnostic studies of BD and MDD in adolescents to reveal the current research status and important directions in the field. Our research and analysis results might provide some practical sources for academic scholars and clinical practice.
... Noteworthy, considering that BD can be often misdiagnosed as UD [78], we observed the occurrence of manic symptoms in one patient part of the UD group, for whom the YMRS was in the clinical range. Nevertheless, all patients included in this study had a long history of disease and a diagnosis confirmed by multiple caregivers of the clinical setting, which reduces the risk of a BD being misdiagnosed as UD [78,85]. ...
Although implicated in unsuccessful treatment, psychomotor deficits and their neurobiological underpinnings in bipolar (BD) and unipolar (UD) depression remain poorly investigated. Here, we hypothesized that motor performance deficits in depressed patients would relate to basal functional coupling of the hand primary motor cortex (M1) and the posterior cingulate cortex (PCC) with the supplementary motor area (SMA). We performed a longitudinal, naturalistic study in BD, UD and matched healthy controls comprising of two resting-state functional MRI measurements five weeks apart and accompanying assessments of motor performance using a finger tapping task (FTT). A subject-specific seed-based analysis describing functional connectivity between PCC-SMA as well as M1-SMA was conducted. The basal relationships with motor performance were investigated using linear regression models and all measures were compared across groups. Performance in FTT was impaired in BD in comparison to HC in both sessions. Behavioral performance across groups correlated significantly with resting state functional coupling of PCC-SMA, but not of M1-SMA regions. This relationship was partially reflected in a reduced PCC-SMA connectivity in BD vs HC in the second session. Exploratory evaluation of large-scale networks coupling (SMN-DMN) exhibited no correlation to motor performance. Our results shed new light on the association between the degree of disruption in the SMA-PCC anticorrelation and the level of motor impairment in BD.
... Similarity in diagnostic criteria between bipolar and unipolar depression makes it difficult for clinicians to make a diagnosis of BD in patients with first episode bipolar depression. Studies have found a misdiagnosis rate of Bipolar Depression as Major Depressive Disorder (MDD) in up to 40% of all BD patients (Ghaemi et al., 1999). The underdiagnosis of BD still continues despite the advances made by DSM 5, with re-analysis of epidemiological studies showing that MDD includes 40% of "hidden" bipolar cases (Angst, 2013). ...
... 66,67 For instance, missing the diagnosis of bipolar disorder is also a common cause of apparent treatment resistance, 68 as antidepressants are then mistakenly prescribed to patients with bipolar depression. 69 A study on the relationship between episode duration and antidepressant therapy concluded that little progress has been made in reducing the length of depressive episodes in bipolar disorder. 70 Regarding comorbid anxiety, the study of Schiffer and colleagues 43 demonstrated that such an associated disorder could adversely affect MDD patients' responsiveness to t-PBM. ...
Major depressive disorder (MDD) is considered a global crisis. Conventional treatments for MDD consist of pharmacotherapy and psychotherapy, although a significant number of patients with depression respond poorly to conventional treatments and are diagnosed with treatment-resistant depression (TRD). Transcranial photobiomodulation (t-PBM) therapy uses near-infrared light, delivered transcranially, to modulate the brain cortex. The aim of this review was to revisit the antidepressant effects of t-PBM, with a special emphasis on individuals with TRD. A search on PubMed and ClinicalTrials.gov tracked clinical studies using t-PBM for the treatment of patients diagnosed with MDD and TRD.
... There is some evidence that differantial diagnosis of bipolar disorder (BD) from unipolar depression (UD) is difficult in the early stages of the disease. It has been reported that 40% of patients diagnosed with BD have been previously diagnosed with unipolar disorder (3,4). Delayed initiation of treatment at illness onset in BD is more likely to result in, social, cognitive and functional limitation than UD (5). ...
Objective: Somatic symptoms are more likely to be present in depression and anxiety, which causes to waste medical resources due to excessive hospital addmissions. It has been observed that the unclarity of qualitative and quantitative characteristics of somatization depending on the type of depression influences clinical practice less than expected. In the present study, it was aimed to determine the hallmarks of somatic symptoms in depression groups and to investigate the factors that might have an effect on somatic symptoms. Method: One hundred consecutive patients (50 with Bipolar Depression (BD), 50 with Unipolar Depression (UD)) who met the criteria participated in the study. Patients were assessed for depressive symptoms with Montgomery Asberg Depression Scale and for somatic symptoms with Bradford Somatic Symptom Inventory. Clinical features were obtained by the clinician via Sociodemographic Data Form. Results: It was found that no significant difference in somatization characteristics between the depression groups. (p> .05). Somatic symptom severity was higher in the UD group in the presence of psychiatric comorbidity (p= .013), but not in BD. Another prominent finding was that the severity of depression was noted the only predictor of severe somatization. Conclusion: The results show that increased somatic symptoms are associated with the severity of depression, suggesting treatment of depression with somatization rather than differential diagnosis should be primary concern.
... 2000; Dunner & Tay, 1993;Hirschfeld, 2001), in part due to patient underreporting of hypomanic 62 episodes (Singh & Rajput, 2006). Diagnosis of BPSD typically follows many years after symptom 63 presentation (Ghaemi, Boiman & Goodwin, 2000;Ghaemi et al., 1999;Mantere et al., 2004), and this 64 diagnostic delay can lead to symptom deterioration and poorer outcomes (Shi, Thiebaud & 65 McCombs, 2004). Even at subclinical levels, hypomanic symptoms can be associated with significant 66 functional impairment (Lewinsohn, Seeley and Klein, 2003), and are a diagnostic antecedent to 67 clinical BPSD (Axelson, et al. 2015). ...
Background. Extreme positive mood characterises (hypo)mania and is associated with increased severity of bipolar disorders. However, the lack of recognition and effective measurement of hypomanic extreme positive mood means it is underreported and poorly understood. As existing affect and hypomanic symptom scales do not specifically measure hypomanic-like affective states, this study begins validation of a new state measure – the Hypomanic Mood Scale. Methods. 468 students completed an online survey consisting of validated state and trait measures of affect and mood disorder symptoms, alongside the novel HMS. Analysis focused on establishing the construct validity, content validity and construct reliability of the HMS.Results. The HMS had a two-factor structure, ‘active-elated’ and ‘irritable-unstable’. The ‘active-elated’ factor was internally reliable, despite overall poor internal consistency of the HMS and poor reliability when hypomanic-like irritation items were included. HMS scores were associated with past and enduring tendencies to experience hypomania, when controlling for current anxiety and depression symptoms. HMS items did not distinguish from general positive mood items on an existing affect scale.Limitations. As a primarily female student sample was used, findings cannot be generalised to general or clinical populations.Conclusions. Findings provide a promising start to the development of a novel hypomanic-like mood scale. Further research should focus on refining the scale and improving internal consistency of the hypomanic-like irritation factor. Successful development and validation of this measure will be useful for future development of simple and accessible methods of self-monitoring mood and tracking risk for patients e.g., medical mobile applications.
... An even greater rate of mis-diagnosis is observed in bipolar disorder of just under 70 percent, with the majority of patients being mis-diagnosed with unipolar depression (34,35). This misidentification rate contributes to documented delays of up to 10 years in receiving an accurate diagnosis of bipolar disorder (34)(35)(36)(37). Delays to accurate diagnosis are associated with significant costs to the individual, such as a poorer response to treatment (38), and increased risk of both substance misuse (39) and suicide attempts (40,41). ...
Digital mental health interventions (DMHI) have the potential to address barriers to face-to-face mental healthcare. In particular, digital mental health assessments offer the opportunity to increase access, reduce strain on services, and improve identification. Despite the potential of DMHIs there remains a high drop-out rate. Therefore, investigating user feedback may elucidate how to best design and deliver an engaging digital mental health assessment. The current study aimed to understand 1304 user perspectives of (1) a newly developed digital mental health assessment to determine which features users consider to be positive or negative and (2) the Composite International Diagnostic Interview (CIDI) employed in a previous large-scale pilot study. A thematic analysis method was employed to identify themes in feedback to three question prompts related to: (1) the questions included in the digital assessment, (2) the homepage design and reminders, and (3) the assessment results report. The largest proportion of the positive and negative feedback received regarding the questions included in the assessment (n = 706), focused on the quality of the assessment (n = 183, 25.92% and n = 284, 40.23%, respectively). Feedback for the homepage and reminders (n = 671) was overwhelmingly positive, with the largest two themes identified being positive usability (i.e., ease of use; n = 500, 74.52%) and functionality (i.e., reminders; n = 278, 41.43%). The most frequently identified negative theme in results report feedback (n = 794) was related to the report content (n = 309, 38.92%), with users stating it was lacking in-depth information. Nevertheless, the most frequent positive theme regarding the results report feedback was related to wellbeing outcomes (n = 145, 18.26%), with users stating the results report, albeit brief, encouraged them to seek professional support. Interestingly, despite some negative feedback, most users reported that completing the digital mental health assessment has been worthwhile (n = 1,017, 77.99%). Based on these findings, we offer recommendations to address potential barriers to user engagement with a digital mental health assessment. In summary, we recommend undertaking extensive co-design activities during the development of digital assessment tools, flexibility in answering modalities within digital assessment, customizable additional features such as reminders, transparency of diagnostic decision making, and an actionable results report with personalized mental health resources.
... The rates of misdiagnosis and its consequences among individuals with mood disorders are well documented. A large proportion of people with BD, ranging from 10% to 70%, are misdiagnosed with MDD (Ghaemi et al., 1999;Hantouche et al., 1998;Lish et al., 1994). Serious consequences for this misdiagnosis include a delay in effective treatment, resulting in poorer vocational and social functioning, and overall poorer quality of life (Awad et al., 2007). ...
There are a variety of educational interventions for families who have a relative with a mental health disorder. However, for those with one or more emotion dysregulation disorders, there are limited options. This article reports on the results of a pilot project using a quasi-experimental design with a sample of 270 (intervention = 217, control = 53) to assess an intervention, Getting Off the Emotional Roller Coaster Skill-Building Family Education Course (GOER Family Course), for families coping with and managing emotion regulation disorders in a loved one which are often misdiagnosed or co-occurring. This intervention was effective in reducing caregiver burden [F(1, 120) = 12.25, p = 0.001], while improving attitudes, knowledge, and skills [F(1, 170) = 6.16, p = 0.014]. It fills an important gap in available resources for families faced with challenges and responsibilities that these disorders can present, especially when inaccurately diagnosed or receiving ineffective treatment. While there is a need for further research and adaptation to virtual learning, the preliminary results show positive effects.
... In the last decade, undetected diagnoses have reached as high as 80% (Fernández et al., 2010). As a further complication, depression is sometimes correctly identified, but manic or hypomanic episodes are not recognized (Ghaemi et al., 1999;Zimmerman et al., 2008), leading to misdiagnoses of depression rather than bipolar disorders (Cerimele et al., 2019). Troublingly, Wittchen et al. (2003) described "diminishing halves" (p. ...
Primary care physicians (PCPs) often daily address diagnoses and treatment of mental disorders in their practices. The current study examined the Connected Mind Fast Check (CMFC), a two-tiered electronic screen, assessing six common mental disorders. The eight-item Initial Screen assesses possible symptoms, whereas SAM modules establish provisional diagnoses and areas of clinical concern. With 234 patients from five independent PCP offices, diagnostic accuracy was tested with the SCID-5-RV as the external criterion. Concerningly, many patients were unaware of their current mental disorders and comorbidities. The CMFC Initial Screen evidenced strong sensitivity, identifying with very few missing diagnoses. About two-thirds of provisional SAM diagnoses were confirmed with high specificities. Bipolar Disorder posed the most challenges at both tiers. Importantly, the suicide screen identified all patients with suicide plans and three-fourths with ideation. In general, the CMFC effectively identified provisional diagnoses, impairment, and potential suicidality.
... Most bipolar patients may not get an accurate diagnosis during the early periods of the disease, as the cycle begins with a period of depression. [99] To diagnose Bipolar Disorder type 1, at least one manic episode is needed. [100] These patients also experience depressive periods, but the presence of manic periods for diagnosis is distinctive. ...
GLP-1 (Glucagon-like peptide-1) receptor agonists have incretin, cardioprotective and neuroprotective effects. Liraglutide, a GLP-1 receptor agonist, is used to treat comorbid diseases such as obesity and diabetes through its incretin and cardioprotective effects. The therapeutic targets of Exenatide on neurodegenerative diseases have recently been concentrated, particularly after the discovery of GLP-1's neuroprotective effects. Mood disorders and metabolic comorbidities are the two groups of diseases that have the greatest global impact on mortality. There is also a significant correlation between patients with mood disorders and patients with obesity and T2DM (Type 2 diabetes mellitus), according to epidemiological data. GLP-1 receptor agonists are exceedingly being used to treat psychological disorders. According to the results of preclinical studies, Liraglutide can prevent cognitive function regression and develop normal functions. This condition suggests that GLP-1 receptor agonists could be useful in the treatment of psychiatric disorders in the future. This review examined the relationship between GLP-1 Receptor Agonists and Psychiatric diseases.
... Similar results were presented in a previous study, 40 where it was noted that these figures were consistent with the high prevalence of misdiagnosis (48% and 69%) found in naturalistic research using self-administered questionnaires in general practitioner consultations 42,43 and also in studies in which diagnoses were based on the application of DSM-IV criteria. 44 However, in our sample, 50.5% of patients who were diagnosed with BD at the first evaluation remained stable in three-quarters of the evaluations. This fact is not consistent with the figure reported by Chen et al, 13 who noted that 70% of the subjects with an initial diagnosis of BD did not change to a different category over time. ...
Objective: Diagnostic stability is the degree to which a diagnosis remains unchanged during time. Our main objective was to evaluate the diagnostic stability of bipolar disorder (BD) in psychiatric outpatient consultations and determine the socio-demographic variables influencing its stability.
Methods: The Cumulative Register of Cases of the Community of Madrid provided data on all outpatient visits conducted at Madrid's Community Mental Healthcare Centers between 1980-2009. Diagnoses were made according to ICD-9/ICD-10 criteria. Two indices were measured: temporal consistency (maintenance of the diagnosis over time) and diagnostic constancy (presence of BD diagnosis in at least 75% of visits). κ coefficient measured the agreement between diagnoses in the first and last evaluations (prospective and retrospective consistency).
Results: 14,557 patients were diagnosed with BD for at least 1 evaluation and had at least 10 visits and 1 year of follow-up. At first evaluation, 3,988 patients were diagnosed with BD (prospective consistency 50.8%), and at last evaluation 5,396 patients were diagnosed with BD (retrospective consistency 37.5%). A total of 2,026 patients were diagnosed with BD at their first and last evaluations (prospective consistency 18.3%).
Conclusions: This longitudinal study conducted in community mental health centers reflects common diagnostic practices in outpatient settings over a 30-year period (130,000 patient-years). Delay of > 10 years was found to achieve diagnostic stability. Frequent diagnostic shifts were found in relation to BD, the most common being with other affective disorders. Anxiety was also a common misdiagnosis. Greater stability was associated with having been diagnosed after hospitalization, having an age at onset > 25 years, and having an age at diagnosis < 24 years.
... The MVPA results showed that the severity levels of FC dimensions have the potential to distinguish MDD and BD with 77% classification accuracy. The accuracy is comparable with that of initial diagnosis by clinical interview (Hantouche et al. 1998;Ghaemi et al. 1999). It suggested that the FC dimension severity levels have the potential to aid the diagnosis of MDD/BD. ...
Literatures have reported considerable heterogeneity with atypical functional connectivity (FC) pattern of psychiatric disorders. However, traditional statistical methods are hard to explore this heterogeneity pattern. We proposed a "brain dimension" method to describe the atypical FC patterns of major depressive disorder and bipolar disorder (BD). The approach was firstly applied to a simulation dataset. It was then utilized to a real resting-state functional magnetic resonance imaging dataset of 47 individuals with major depressive disorder, 32 individuals with BD, and 52 well matched health controls. Our method showed a better ability to extract the FC dimensions than traditional methods. The results of the real dataset revealed atypical FC dimensions for major depressive disorder and BD. Especially, an atypical FC dimension which exhibited decreased FC strength of thalamus and basal ganglia was found with higher severity level of individuals with BD than the ones with major depressive disorder. This study provided a novel "brain dimension" method to view the atypical FC patterns of major depressive disorder and BD and revealed shared and specific atypical FC patterns between major depressive disorder and BD.
... It is a disorder that is often diagnosed late. A diagnosis could take as long as 10 years, but the mean delay is estimated to be around 6.5 years [4][5][6]. It has been suggested that the delay is shorter if non-specialist mental health professionals can detect symptoms before specialist teams assessed them [7]. ...
Mixed states are highly prevalent in patients with bipolar disorder and require comprehensive scales. Considering this, the current study aims to develop a measure to assess the full spectrum of clinical manifestations of bipolar disorder. A sample of 88 patients was evaluated; the Hamilton Depression Scale (HAM-D), Montgomery-Asberg Depression Scale (MADRS), and the Young Mania Rating Scale (YMRS) were applied, together with the preliminary version of the Scale for the Assessment of Episodes in Bipolar Disorder (SAEBD). After analyzing the appropriateness and statistical properties of the items, discriminant analysis and analysis of diagnostic capacity were performed. The discriminant functions correctly classified 100% of the cases in euthymia, predominant depressive symptoms or mixed symptoms, as well as 92.3% of the cases with predominant manic symptoms. Overall, the functions correctly classified 98.9% of the cases. The area under the curve (0.935) showed high capacity to discriminate between clinical and non-clinical cases (i.e., in euthymia). The SAEBD sensitivity was 0.95, specificity was 0.71, the Positive Predictive Value (PPV) was 0.88, the Negative Predictive Value (NPV) was 0.87, the Positive Likelihood Ratio (+LR) was 3.33, and the Negative Likelihood Ratio (LR) was 0.07. In conclusion, the SAEBD is a promising scale that shows high reliability and validity, as well as diagnostic utility as a screening tool for use in diverse health care settings.
Abstract: https://www.mdpi.com/1660-4601/18/16/8318
HTML Version: https://www.mdpi.com/1660-4601/18/16/8318/htm
PDF Version: https://www.mdpi.com/1660-4601/18/16/8318/pdf
... Bipolar disorder is long known to be under-diagnosed. 58 When cancer patients complain of depressive symptoms, if psychooncologists regard their distress simply as a reaction to cancer diagnosis or treatment, the diagnosis of bipolar disorder can be missed. We suggest that bipolar disorder be ruled out before making a diagnosis of unipolar depression, particularly in patients with cancers that occur primarily in women. ...
Objective:
We aimed to determine the overall profile of patients in a psycho-oncology clinic and the differences in their characteristics according to the cancer site.
Methods:
The charts of 740 patients aged under 81 years were reviewed. The data from 586 completed questionnaires were subjected to multiple comparison analyses using one-way analysis of variance to examine the demographic and clinical differences according to the cancer site.
Results:
Most (n=532, 71.9%) patients were referred. Most new patients (n=426, 96.6%) received a psychiatric diagnosis; the most common diagnosis was depressive disorder (n=234, 31.6%). Likewise, depressive disorder accounted for the majority of diagnoses in all groups except for the digestive system cancer group in which sleep-wake disorder was the most prevalent. The female genital cancer group showed a higher level of anxiety symptoms than other groups, except for breast and haematolymphoid cancer groups, and psychological distress than all other groups.
Conclusion:
There appear to be delays in the referral of cancer patients seeking psychiatric help to a psycho-oncology clinic. Along with tailoring approaches by cancer site, thorough evaluation and appropriate management of sleep-wake and anxiety symptoms are important for digestive system and female genital cancer patients, respectively.
... Both disorders are associated with elevated suicide rates, self-harm, and other severe aspects, such as: longer hospital stay, higher rates of abandonment, and greater use of medication. (10)(11)(12)(13)(14)(15)(16)(17)(18) Around 20% of patients diagnosed with BPAD or BPD are diagnosed with the other. The prevalence of BPAD in subjects with BPD varies from 5.1% to 78.9%, which is higher compared to bipolar I disorder and bipolar II disorder. ...
Introduction: Bipolar disorder and borderline personality disorder are diagnoses that have a wide variety of symptoms. However, it is described that the comorbidity of both intensifies the clinical severity due to the appearance of a greater number of suicide attempts or self-harm. The objective of the study was to determine and compare the sociodemographic characteristics, clinical severity, and symptoms in patients within these 3 groups. Method: the study was descriptive and qualitative, observational and transversal design. A sample of 92 clinical records of patients treated at the National Hospital Víctor Larco Herrera from January 2010 to May 2018 was used. Sociodemographic variables (age, sex, marital status, religion, level of education and occupation) and clinical severity (number of hospitalizations, suicide attempts, refusal of medication, response to treatment, substance abuse, current hospitalization and severity symptoms) using a data collection form. Results: The sociodemographic variables with statistical significance and higher frequency were female sex (p = 0.049), single marital status (p=0.003), catholic religion (p = 0.009), as well as the variables of clinical severity with statistical significance were the number of hospitalizations (p = 0.015), psychotic symptoms (p = 0.009), irritability (p = 0.038), impairment (p = 0.000) and number of symptoms of severity (p = 0.030) in TB, BPD and their comorbidity. Conclusions: The clinical severity is associated with the number of hospitalizations, the presence of psychotic symptoms, irritability, dysfunctionality and the number of severe symptoms in patients with only TB diagnosis, BPD and their comorbidity.
... The odds ratios increased with a greater number of major depression risk alleles, and an odds ratio of 2.4 was observed in the tenth versus the first PRS decile [41], which suggests that the use of PRS allows the stratification of individuals according to their disease risk. In the long term, one conceivable application of PRS in affective disorders would be an improved differentiation between a unipolar and a bipolar disease course, since around 40 % of bipolar disorder patients are initially diagnosed with major depression [78,79]. The early prediction of disease course might also be clinically relevant, since research has shown that patients who are ultimately diagnosed with bipolar disorder are less likely to respond to antidepressant treatment for an acute depressive phase than patients with purely major depression [80]. ...
Affective disorders, or mood disorders, are a group of neuropsychiatric illnesses that are characterized by a disturbance of mood or affect. Most genetic research in this field to date has focused on bipolar disorder and major depression. Symptoms of major depression include a depressed mood, reduced energy, and a loss of interest and enjoyment. Bipolar disorder is characterized by the occurrence of (hypo)manic episodes, which generally alternate with periods of depression. Formal and molecular genetic studies have demonstrated that affective disorders are multifactorial diseases, in which both genetic and environmental factors contribute to disease development. Twin and family studies have generated heritability estimates of 58-85 % for bipolar disorder and 40 % for major depression. Large genome-wide association studies have provided important insights into the genetics of affective disorders via the identification of a number of common genetic risk factors. Based on these studies, the estimated overall contribution of common variants to the phenotypic variability (single-nucleotide polymorphism [SNP]-based heritability) is 17-23 % for bipolar disorder and 9 % for major depression. Bioinformatic analyses suggest that the associated loci and implicated genes converge into specific pathways, including calcium signaling. Research suggests that rare copy number variants make a lower contribution to the development of affective disorders than to other psychiatric diseases, such as schizophrenia or the autism spectrum disorders, which would be compatible with their less pronounced negative impact on reproduction. However, the identification of rare sequence variants remains in its infancy, as available next-generation sequencing studies have been conducted in limited samples. Future research strategies will include the enlargement of genomic data sets via innovative recruitment strategies; functional analyses of known associated loci; and the development of new, etiologically based disease models. Researchers hope that deeper insights into the biological causes of affective disorders will eventually lead to improved diagnostics and disease prediction, as well as to the development of new preventative, diagnostic, and therapeutic strategies. Pharmacogenetics and the application of polygenic risk scores represent promising initial approaches to the future translation of genomic findings into psychiatric clinical practice.
... To this end, three patient groups were recruited. The first group comprised patients with current depressive symptoms who had recently (≤5 years) (Ghaemi et al., 1999;Morselli et al., 2003) been diagnosed with MDD, the second group comprised participants with current depressive symptoms and no lifetime mood disorder diagnosis, and the third group comprised patients with current depressive symptoms and a previous lifetime BD diagnosis (Figure 1). The study was approved by the University of Cambridge Human Biology Research Ethics Committee (approval number HBREC 2017.11) and was con- ...
Objectives
The Delta Study was undertaken to improve the diagnosis of mood disorders in individuals presenting with low mood. The current study aimed to estimate the prevalence and explore the characteristics of mood disorders in participants of the Delta Study, and discuss their implications for clinical practice.
Methods
Individuals with low mood (Patients Health Questionnaire‐9 score ≥5) and either no previous mood disorder diagnosis (baseline low mood group, n = 429), a recent (≤5 years) clinical diagnosis of MDD (baseline MDD group, n = 441) or a previous clinical diagnosis of BD (established BD group, n = 54), were recruited online. Self‐reported demographic and clinical data were collected through an extensive online mental health questionnaire and mood disorder diagnoses were determined with the World Health Organization Composite International Diagnostic Interview (CIDI).
Results
The prevalence of BD and MDD in the baseline low mood group was 24% and 36%, respectively. The prevalence of BD among individuals with a recent diagnosis of MDD was 31%. Participants with BD in both baseline low mood and baseline MDD groups were characterized by a younger age at onset of the first low mood episode, more severe depressive symptoms and lower wellbeing, relative to the MDD or low mood groups. Approximately half the individuals with BD diagnosed as MDD (49%) had experienced (hypo)manic symptoms prior to being diagnosed with MDD.
Conclusions
The current results confirm high under‐ and misdiagnosis rates of mood disorders in individuals presenting with low mood, potentially leading to worsening of symptoms and decreased well‐being, and indicate the need for improved mental health triage in primary care.
... An addiction to SNS's can lead to mood disorders. Even though mood disorders are basic public health problems, they are recurrent and chronic disorders that cannot be correctly diagnose even in psychiatric clinics (Ghaemi, Sachs, Chiou, Pandurangi& Goodwin, 1999). Non-conformity between two opposite poles, such as person's social network identity and real personality, can provoke pathological experiences. ...
Living in the age of constant technology developments shifted social communication patterns and shifted social relations to virtual environments. The socialisation process that takes place in digital platforms also transferred many negative elements experienced in social life to the virtual environment. That is, the aggression behaviours concerning these negative processes have also been transferred to the virtual communication. The current study examines the effects of social media aggression (SMA) regarding digital platforms on the social relations in human life in the context of various variables. Results of the study revealed that the counter-comments towards participants’ values have a significant effect on participants’ demonstration of aggressive tendencies. In other notable finding participants reported that they aware of their rights f=75 (33%) against negative SMA, while f=150 (67%) of participants do not know them. Keywords: Virtual communication, social media, aggression.
... Literature describes both over-and underdiagnosis of bipolar disorder (36)(37)(38) largely depending on mental health infrastructure, habits, and whether diagnosis is made according to patient reports or formalized interviews and criteria. But what is the real need to add up symptoms for the gate criterion A to correctly identify bipolar patients? ...
According to DSM-IV, the criterion (A) for diagnosing hypomanic/manic episodes is mood change (i.e., elevated, expansive or irritable mood). Criterion (A) was redefined in DSM-5 in 2013, adding increased energy/activity in addition to mood change. This paper examines a potential change of prevalence data for bipolar I or II when adding increased energy/activity to the criterion (A) for the diagnosis of hypomania/mania. Own research suggests that the prevalence of manic/hypomanic episodes drops by at least one third when using DSM-5 criteria. Whether this has positive or negative impact on clinical practice and research still needs further evaluation.
... Both disorders are associated with impaired functioning (Kessler et al., 2006;Morgan, Mitchell, & Jablensky, 2005;Skodol et al., 2002;Zanarini, Jacoby, Frankenburg, Reich, & Fitzmaurice, 2009), increased use of health care services (Bender et al., 2001;Bryant-Comstock, Stender, & Devercelli, 2002;Zanarini, Frankenburg, Hennen, & Silk, 2004), increased rates of substance use disorders (Di Florio, Craddock, & van den Bree, 2014;Farren, Hill, & Weiss, 2012;Trull, Sher, Minks-Brown, Durbin, & Burr, 2000), and suicidality (Baldessarini, Pompili, & Tondo, 2006;Joyce, Light, Rowe, Cloninger, & Kennedy, 2010;Novick, Swartz, & Frank, 2010;Oldham, 2006;Pompili, Girardi, Ruberto, & Tatarelli, 2005). Patients with bipolar disorder or BPD most commonly present for the treatment of depression (Zimmerman, Chelminski, Dalrymple, & Rosenstein, 2017), therefore, it is not surprising that both disorders are frequently underdiagnosed (Ghaemi, Sachs, Chiou, Pandurangi, & Goodwin, 1999;Zimmerman & Mattia, 1999a, 1999b. Calls for improved recognition have been voiced for both disorders (Dunner, 2003;Zimmerman, 2015). ...
... Both disorders are associated with impaired functioning (Kessler et al., 2006;Morgan, Mitchell, & Jablensky, 2005;Skodol et al., 2002;Zanarini, Jacoby, Frankenburg, Reich, & Fitzmaurice, 2009), increased use of health care services (Bender et al., 2001;Bryant-Comstock, Stender, & Devercelli, 2002;Zanarini, Frankenburg, Hennen, & Silk, 2004), increased rates of substance use disorders (Di Florio, Craddock, & van den Bree, 2014;Farren, Hill, & Weiss, 2012;Trull, Sher, Minks-Brown, Durbin, & Burr, 2000), and suicidality (Baldessarini, Pompili, & Tondo, 2006;Joyce, Light, Rowe, Cloninger, & Kennedy, 2010;Novick, Swartz, & Frank, 2010;Oldham, 2006;Pompili, Girardi, Ruberto, & Tatarelli, 2005). Patients with bipolar disorder or BPD most commonly present for the treatment of depression (Zimmerman, Chelminski, Dalrymple, & Rosenstein, 2017), therefore, it is not surprising that both disorders are frequently underdiagnosed (Ghaemi, Sachs, Chiou, Pandurangi, & Goodwin, 1999;Zimmerman & Mattia, 1999a, 1999b. Calls for improved recognition have been voiced for both disorders (Dunner, 2003;Zimmerman, 2015). ...
... In fact,~37% of patients with BD who present after their first manic/hypomanic episode are nonetheless misdiagnosed as having MDD 7 . Overall, it is estimated that at least 19% of individuals experiencing a major depressive episode have BD 8 , and that~40% of patients with BD are initially diagnosed with MDD 7,9 , with the average delay in BD diagnosis ranging from 5.7 to 7.5 years 10,11 . As a result, misdiagnosed patients with BD are often incorrectly treated with antidepressants, which can aggravate the disease and worsen the outcomes 12 . ...
The vast personal and economic burden of mood disorders is largely caused by their under- and misdiagnosis, which is associated with ineffective treatment and worsening of outcomes. Here, we aimed to develop a diagnostic algorithm, based on an online questionnaire and blood biomarker data, to reduce the misdiagnosis of bipolar disorder (BD) as major depressive disorder (MDD). Individuals with depressive symptoms (Patient Health Questionnaire-9 score ≥5) aged 18–45 years were recruited online. After completing a purpose-built online mental health questionnaire, eligible participants provided dried blood spot samples for biomarker analysis and underwent the World Health Organization World Mental Health Composite International Diagnostic Interview via telephone, to establish their mental health diagnosis. Extreme Gradient Boosting and nested cross-validation were used to train and validate diagnostic models differentiating BD from MDD in participants who self-reported a current MDD diagnosis. Mean test area under the receiver operating characteristic curve (AUROC) for separating participants with BD diagnosed as MDD ( N = 126) from those with correct MDD diagnosis ( N = 187) was 0.92 (95% CI: 0.86–0.97). Core predictors included elevated mood, grandiosity, talkativeness, recklessness and risky behaviour. Additional validation in participants with no previous mood disorder diagnosis showed AUROCs of 0.89 (0.86–0.91) and 0.90 (0.87–0.91) for separating newly diagnosed BD ( N = 98) from MDD ( N = 112) and subclinical low mood ( N = 120), respectively. Validation in participants with a previous diagnosis of BD ( N = 45) demonstrated sensitivity of 0.86 (0.57–0.96). The diagnostic algorithm accurately identified patients with BD in various clinical scenarios, and could help expedite accurate clinical diagnosis and treatment of BD.
... Treatment of these patients for unipolar depression may also increase the risk of manic state [3]. Previous studies have suggested that almost 40% of patients with bipolar disorder were misdiagnosed with unipolar depression or psychosis [4,5]. On the other hand, underdiagnosis remains a significant problem, which causes undertreatment and may worsen the outcome of bipolar disorder [5]. ...
Aim: Irisin is a myokine and adipokine which has neural effects such as playing a role in neural proliferation. There are studies in the literature reporting that irisin could be associated with neurodegenerative processes. Therefore, in this study, we aimed to evaluate the irisin levels in patients with bipolar depression and major depressive disorder. Materials and Methods: Thirty patients with bipolar disorder (BD) depressive episodes, 28 patients with major depressive disorder (MDD) and 30 healthy controls (HCs) were included in the study. Sociodemographic and clinical data were collected from each participant. Serum irisin levels were determined by enzyme-linked immunosorbent assay (ELISA) kits, and the severity of the depression was measured by the Hamilton Depression Rating Scale. Results: There was no statistically significant difference between patients with MDD, bipolar disorder depressive episodes and healthy controls in terms of irisin levels. The statistical analysis revealed significant negative correlations between levels of irisin and duration of illness (r=−0.500, p<0.01) in MDD. Irisin serum level was found to be negatively correlated with the number of depressive episodes (r=-0.620, p<0.01) in patients with MDD. Discussion: Irisin's role in the development of depression in patients with coronary artery diseases and patients having strokes has been studied previously in the literature. Our study is the first that evaluated levels of irisin in patients with bipolar depression and major depressive disorder. No statistically significant difference was obtained in these three groups in terms of irisin levels. Further studies may help to understand the role of irisin in the underlying mechanism of depression.
... BD affects 1-3% of the world's population, irrespective of diverse nationality, ethnicity, or socioeconomic status (Merikangas et al., 2011;Pedersen et al., 2014). Because depressive episodes are generally more frequent in BD and BD patients are much more likely to visit clinicians in outpatient setting when they are depressed (Angst et al., 2011), many individuals with BD are initially misdiagnosed as unipolar major depressive disorder (MDD) (Hirschfeld, Cass, Holt, & Carlson, 2005;Hirschfeld, Lewis, & Vornik, 2003), and they may receive inappropriate medications before presenting hypomanic or manic symptoms (Bowden, 2005;Ghaemi, Sachs, Chiou, Pandurangi, & Goodwin, 1999;Lish, Dime-Meenan, Whybrow, Price, & Hirschfeld, 1994;Morselli, Elgie, & Europe, 2003). For accurate diagnosis and treatment, it is imperative to identify valid and reliable biomarkers for this disorder. ...
Background:
An aberrant neural connectivity has been known to be associated with bipolar disorder (BD). Local gyrification may reflect the early neural development of cortical connectivity and has been studied as a possible endophenotype of psychiatric disorders. This study aimed to investigate differences in the local gyrification index (LGI) in each cortical region between patients with BD and healthy controls (HCs).
Methods:
LGI values, as measured using FreeSurfer software, were compared between 61 patients with BD and 183 HCs. The values were also compared between patients with BD type I and type II as a sub-group analysis. Furthermore, we evaluated whether there was a correlation between LGI values and illness duration or depressive symptom severity in patients with BD.
Results:
Patients with BD showed significant hypogyria in various cortical regions, including the left inferior frontal gyrus (pars opercularis), precentral gyrus, postcentral gyrus, superior temporal cortex, insula, right entorhinal cortex, and both transverse temporal cortices, compared to HCs after the Bonferroni correction (p < 0.05/66, 0.000758). LGI was not associated with clinical factors such as illness duration, depressive symptom severity, and lithium treatment. No significant differences in cortical gyrification according to the BD subtype were found.
Conclusions:
BD appears to be characterized by a significant regionally localized hypogyria, in various cortical areas. This abnormality may be a structural and developmental endophenotype marking the risk for BD, and it might help to clarify the etiology of BD.
Background
A comparison of the clinical course and symptom profile of unipolar (UP) and bipolar (BP) depression reveals many similarities as well as subtle differences between the two syndromes. Phenomenological and clinical features that would distinguish BP from UP depression can help in appropriate and early treatment. This could, in turn, influence the choice of treatment, clinical course, and outcomes. Misdiagnosing BP depression as a major depressive disorder early may result in manic switch and/or rapid cycling. Most of the published literature in this area is from the Western world. We, therefore, aimed to study phenomenology, clinical factors, and substance use among patients with BP and UP depression. This study would potentially contribute to the existing literature and help in better diagnosis and treatment.
Aim and Objectives
The aim of this study was to assess the clinical profile and substance use among patients with UP and BP depression and to determine the predictors of bipolarity.
Materials and Methods
Fifty patients with BP and 50 with UP depression who satisfied the International Classification of Diseases, tenth edition criteria were included in our study. We assessed our participants using the Hamilton Rating Scale for Depression, Brief Psychiatric Rating Scale, Alcohol Use Disorders Identification Test, Fagerstrom Test for Nicotine Dependence, and a self-designed, semi-structured pro forma for obtaining sociodemographic, clinical, and substance use profiles.
Results
Younger males with a greater number of episodes, earlier onset of illness, greater number of hospitalizations, and higher psychotic symptoms were found in our BP depression group. Logistic regression identified male gender, family history of substance use, history of alcohol dependence, ideas of guilt, forgetfulness, psychomotor agitation, deliberate self-harm, delusion, and hallucinations as predictors of bipolarity (odds ratio = 2.97; 2.25; 9.06; 2.45; 2.43; 16.97; 7.11; 9.33; and 11.46, respectively).
Conclusions
Young male individuals with a history of substance use, psychotic symptoms, and psychomotor agitation should be carefully evaluated for bipolarity. We need prospective studies with a large sample size to identify early clinical markers of bipolarity.
Background:
It is clinically important to predict the conversion of major depression (MD) to bipolar disorder (BD). Therefore, we sought to identify related conversion rates and risk factors.
Methods:
This cohort study included the Swedish population born from 1941 onward. Data were collected from Swedish population-based registers. Potential risk factors, including family genetic risk scores (FGRS), which were calculated based on the phenotypes of relatives in the extended family and not molecular data, and demographic/clinical characteristics from these registers were retrieved. Those with first MD registrations from 2006 were followed up until 2018. The conversion rate to BD and related risk factors were analyzed using Cox proportional hazards models. Additional analyses were performed for late converters and with stratification by sex.
Results:
The cumulative incidence of conversion was 5.84% [95% confidence interval (95% CI) 5.72-5.96] for 13 years. In the multivariable analysis, the strongest risk factors for conversion were high FGRS of BD [hazard ratio (HR) = 2.73, 95% CI 2.43-3.08], inpatient treatment settings (HR = 2.64, 95% CI 2.44-2.84), and psychotic depression (HR = 2.58, 95% CI 2.14-3.11). For late converters, the first registration of MD during the teenage years was a stronger risk factor when compared with the baseline model. When the interactions between risk factors and sex were significant, stratification by sex revealed that they were more predictive in females.
Conclusions:
Family history of BD, inpatient treatment, and psychotic symptoms were the strongest predictors of conversion from MD to BD.
Objectives:
To elucidate the relationship between the course of bipolar disorder (BD) and structural brain changes across the life span, we conducted a systematic review of longitudinal imaging studies in adolescent and adult BD-patients.
Methods:
Eleven studies with 329 BD-patients and 277 controls met our PICOS-criteria (participants, intervention, comparison, outcome, study design): BD-diagnosis based on DSM criteria, natural course of disease, comparison of grey matter changes in BD-individuals over ≥1 year interval between scans.
Results:
The selected studies yielded heterogeneous findings, partly due to varying patient characteristics, data acquisition and statistical models. Mood episodes were associated with greater grey matter loss in frontal brain regions over time. Brain volume decreased or remained stable in paediatric patients, whereas it increased in healthy children and adolescents. Adult BD-patients showed increased cortical thinning and brain structural decline. In particular, disease onset in adolescence was associated with amygdala volume reduction, which was not reported in adult BD.
Conclusions:
The evidence collected suggests that the progression of BD impairs paediatric brain development and accelerates structural brain decline across the lifespan. Age-specific changes in amygdala volume in paediatric BD suggests that reduced amygdala volume is a correlate of early onset BD. Clarifying the role of BD in brain-development across the life span promises a deeper understanding of the progression of BD patients through different developmental episodes.
In this study, we aimed to differentiate between euthymic bipolar disorder (BD) patients and healthy controls (HC) based on frontal activity measured by fNIRS that were converted to spectrograms with Convolutional Neural Networks (CNN). And also, we investigated brain regions that cause this distinction. In total, 29 BD patients and 28 HCs were recruited. Their brain cortical activities were measured using fNIRS while performing letter versions of VFT. Each one of the 24 fNIRS channels was converted to a 2D spectrogram on which a CNN architecture was designed and utilized for classification. We found that our CNN algorithm using fNIRS activity during a VFT is able to differentiate subjects with BD from healthy controls with 90% accuracy, 80% sensitivity, and 100% specificity. Moreover, validation performance reached an AUC of 94% From our individual channel analyses, we observed channels corresponding to the left inferior frontal gyrus (left-IFC), medial frontal cortex (MFC), right dorsolateral prefrontal cortex (DLPFC), Broca area, and right premotor have considerable activity variation to distinguish patients from HC. fNIRS activity during VFT can be used as a potential marker to classify euthymic BD patients from HCs. Activity particularly in the MFC, left-IFC, Broca's area, and DLPFC have a considerable variation to distinguish patients from healthy controls.
Background
There is an increasing interest about the role of miRNAs in the pathogenesis of bipolar disorder (BD). In this study, we aimed to examine the role of miRNAs as potential diagnostic and clinical biomarkers in BD.
Methods
Fifteen miRNAs in plasmas obtained from BD patients (n = 66) and from the healthy control group (n = 66) were analyzed by a qPCR test. Clinical variables including lithium treatment response were assessed with various test batteries. The correlation of the miRNA levels with the clinical variables and scale scores was examined. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the DIANA-miRPath v.3.0 software to identify the possible target genes.
Results
The miR-132, miR-134, miR-152, miR-607, miR-633, and miR-652 levels were significantly increased, whereas the miR-15b and miR-155 levels were found to be significantly decreased in the patient group compared to the controls. The miR-15b-5p and miR-155-5p levels and increases in the miR-134-5p and miR-652-3p levels were calculated to have 83.3 % sensitivity and 78.8 % specificity in determining the risk of BD. miR-155-5p was associated with the disease burden and severity. Fatty acid biosynthesis and metabolism, viral carcinogenesis, the EBV infection, and extracellular matrix and adhesion pathways were highlighted as target pathways.
Conclusion
We can conclude that miRNAs may play a role in the pathophysiology of BD through various biological pathways and that miRNAs may be used as a screening test to distinguish bipolar patients from healthy controls. Our findings will provide a basis for long-term follow-up studies with larger samples.
The diagnosis of bipolar disorder (BO) is crucial, for it is now recognized as a condition with high prevalence and serious cognitive deficits. However, it is often misdiagnosed as major depressive disorder (MOO) for its similar symptomatology. The indicated subsequent issue of misdiagnosis to MOO is the improper prescription of antidepressant monotreatment, a one-directional medication for a two-directional disorder. This review provides a comprehensive overview of the similar pathophysiological mechanism behind both disorders, specifically in the BONF pathway. Moreover, its subsequent detrimental effects on the adolescent brains of misdiagnosed pediatric BO patients will be discussed from a developmental perspective.
Background
Patients with bipolar disorder are often unrecognised and misdiagnosed with major depressive disorder leading to higher direct costs and pressure on the medical system. Novel screening tools may mitigate the problem. This study was aimed at investigating the direct costs of bipolar disorder misdiagnosis in the general population, evaluating the impact of a novel bipolar disorder screening algorithm, and comparing it to the established Mood Disorder Questionnaire. A decision analysis model was built to quantify the utility of one-time screening for bipolar disorder in primary care adults presenting with a depressive episode. A hypothetical population of interest comprised a healthcare system of one million users, corresponding to 15,000 help-seekers diagnosed with major depressive disorder annually, followed for five years. The model was used to calculate the impact of screening for bipolar disorder, compared to no screening, in terms of accuracy and total direct costs to a third-party payer at varying diagnostic cut-offs. Decision curve analysis was used to evaluate clinical utility.
Results
Compared to no screening, one-time screening for bipolar disorder using the algorithm reduced the number of misdiagnoses from 680 to 260, and overall direct costs from $50,936 to $49,513 per patient, accounting for $21.3 million savings over the five-year period. The algorithm outperformed the Mood Disorder Questionnaire, which yielded 367 misdiagnoses and $18.3 million savings over the same time. Decision curve analysis showed the screening model was beneficial.
Conclusions
Utilisation of bipolar disorder screening strategies could lead to a substantial reduction in human suffering by reducing misdiagnosis, and also lessen the healthcare costs.
This study aimed to explore the role of C-reactive protein (CRP) in the pathological mechanism and differential diagnoses of bipolar disorder (BD) and unipolar depression (UD). We tested serum CRP levels of 176 BD and 86 UD patients, and 82 healthy controls (HCs), at acute and remission phases. In the acute phase, CRP levels were higher in BD than in UD patients and HC, and lower in UD patients than in HC. The CRP levels of BD patients in a manic episode were higher than those of HC; in a depressive or mixed episode, they were comparable to those of HC. The CRP levels of BD and UD patients during an acute depressive episode yielded an area under the curve of 0.676. CRP may be a state marker of acute manic episodes in BD and acute depressive episodes in UD, and a biomarker for distinguishing BD and UD.
Underpinnings of psychomotor deficits in bipolar and unipolar depression remain underexplored. Here, we hypothesize that motor performance deficits in patients may be partially explained by altered functional connectivities between hand primary motor cortex and posterior cingulate cortex with supplementary motor area.
95 participants between 18-65 years of age, including bipolar depressed, unipolar depressed, and sex-, age-, and education-matched healthy controls, participated in this observational study with two separate visits about five weeks apart, during which the patients received psychopharmacological treatment. Motor performance was measured with a finger-tapping-task and related to functional connectivity from individual seeds in hand primary motor cortex and posterior cingulate cortex as well as to the default mode and sensory motor networks from resting state functional MRI data.
79 participants (45.6% females, 21 bipolar depressed, 27 unipolar depressed and 31 healthy controls) were included in the analysis. Using a finger-tapping-task, the groups differed in motor performance (ANOVA factor group F(2,76) = 4.122; p = 0.020) and bipolar depressed but not unipolar depressed showed performance deficits compared to controls (post-hoc-test p = 0.023 and p = 0.158 respectively). Behavioral performance correlated with functional coupling of posterior cingulate cortex - supplementary motor area, but not with coupling of primary motor cortex - supplementary motor area at cluster-wise correction level p FWEc < 0.05. Correlation differences were seen in posterior cingulate cortex - supplementary motor area (healthy controls>bipolar depressed, unipolar depressed>bipolar depressed) at second visit and in primary motor cortex - supplementary motor area (bipolar depressed>unipolar depressed) at both visits at cluster-wise correction level p FWEc<0.05. Motor performance did not relate to functional coupling of sensory motor network - anterior (visit 1 p = 0.375, visit 2 p = 0.700) or - posterior (visit 1 p = 0.903, visit 2 p = 0.772) default mode network.
Motor performance deficits were seen exclusively in bipolar depressed and related to reduced posterior cingulate cortex - supplementary motor area functional connectivity at rest. Our results shed new light on a possible disruption in the anticorrelation between these regions, which seems fundamental for the preservation of motor skills. Given that nuisance factors were controlled for in the study, it is unlikely that the main results are biased by lefthanders, medication load, seed volumes, or differences in movements during MRI scanning. If these findings are confirmed, new targeted non-invasive interventions, such as repetitive transcranial magnetic stimulation, may be more effective against psychomotor deficits in bipolar depression, when aimed at modulating the supplementary motor area.
Background
Previous studies have shown that bipolar disorder (BD) patients frequently present with difficulties in interpersonal relationships, education or employment and suffer poorer quality of life. This study aimed to estimate the impact of BD on health-related quality of life (HRQOL), work productivity loss and indirect costs.
Methods
Data was from the online, self-administered 2019 National Health and Wellness Survey. Outcomes were compared for those who self-reported a physician diagnosis of BD (N=179), major depressive disorder (MDD, N=1,549) and controls who have never experienced BD, MDD and schizophrenia (N=27,485).
Results
The lifetime prevalence was estimated to be 0.60% for BD and 5.16% for MDD. Significantly lower Mental Component Summary (MCS), Role Component Summary (RCS) scores and EuroQol 5-dimension scale (EQ-5D-5L) summary index and significantly higher presenteeism, total work productivity impairment and activity impairment assessed by Work Productivity and Activity Impairment questionnaire and indirect costs for BD versus controls and BD PHQ-9≥10 versus PHQ-9<10 were observed. Compared to MDD patients, BD patients had significantly lower RCS score and greater work productivity loss and activity impairment. The national morbidity cost of BD in Japan was estimated to be Japanese yen 1,236 billion using a human-capital approach.
Limitations
The data used were self-reported and is cross-sectional in nature, thus causal relationship cannot be assumed.
Conclusion
BD patients and those with severe depressive symptoms experience significantly poorer HRQOL and greater work productivity loss and indirect costs. These findings highlight the importance of proper screening, diagnosis and treatment of BD and bipolar depression.
Background
Major depressive and bipolar disorders are associated with impaired quality of life and high economic burden. Although progress has been made in our understanding of the underlying pathophysiology and the development of novel pharmacological treatments, a large unmet need remains for finding effective treatment options. The purpose of this study was to identify potential new mechanisms of actions or treatment targets that could inform future research and development opportunities for major depressive and bipolar disorders.
Methods
A self-controlled cohort study was conducted to examine associations between 1933 medications and incidence of major depressive and bipolar disorders across four US insurance claims databases. Presence of incident depressive or bipolar disorders were captured for each patient prior to or after drug exposure and incident rate ratios were calculated. Medications that demonstrated ≥50% reduction in risk for both depressive and bipolar disorders within two or more databases were evaluated as potential treatment targets.
Results
Eight medications met our inclusion criteria, which fell into three treatment groups: drugs used in substance use disorders; drugs that affect the cholinergic system; and drugs used for the management of cardiovascular-related conditions.
Limitations
This study was not designed to confirm a causal association nor inform current clinical practice. Instead, this research and the methods employed intended to be hypothesis generating and help uncover potential treatment pathways that could warrant further investigation.
Conclusions
Several potential drug targets that could aid further research and discovery into novel treatments for depressive and bipolar disorders were identified.
Background:
Depression is one of the leading causes of premature death and disability. However, both unipolar and bipolar depression are underdiagnosed and undertreated. The aims of this study were to assess medical students' level of confidence in and knowledge of diagnosing and treating depression before and after completing a psychiatry clerkship, and their knowledge of differentiating unipolar vs bipolar depression.
Methods:
Third-year medical students at Augusta University (Georgia, USA) completed an online questionnaire to assess confidence in and knowledge of diagnosing and treating unipolar and bipolar depression.
Results:
Students who completed a psychiatry clerkship were statistically significantly more comfortable/confident with diagnosing (P < .0001) and treating (P < .0001) unipolar depression. Regarding bipolar depression, 73% of students who completed a psychiatry clerkship correctly diagnosed bipolar disorder, vs 59% of students who did not complete a psychiatry clerkship. This difference was not statistically significant (P = .181).
Conclusions:
Students who completed a psychiatry clerkship were more confident in diagnosing and treating unipolar depression compared with those who did not complete a psychiatry clerkship. However, there was no statistically significant difference between students who had completed a psychiatry clerkship and those who had not completed a psychiatry clerkship in making the correct diagnosis of bipolar depression. Neither group had a very high rate of correct diagnosis.
In the past few years, significant progress has been made in characterizing the function of the gut–brain axisGut–brain axis, i.e., the interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. Preclinical studies described the important role of the gut microbiota in gut brain interactions Furthermore, gut microbiome has been linked to various serious mental illnesses, such as schizophrenia, bipolar disorder, anxiety disorders, depression. This chapter will describe the possible mechanisms that enhance the connection between them and the gut microbiome.
Bipolar disorder (BD) diagnosis currently relies on assessment of clinical symptoms, mainly retrospective and subject to memory bias. BD is often misdiagnosed as Major Depressive Disorder (MDD) resulting in ineffective treatment and worsened clinical outcome. The primary purpose of this study was to identify blood biomarkers that discriminate MDD from BD patients when in a depressed state. We have used clinical data and serum samples from two independent naturalistic cohorts of patients with a Major Depressive Episode (MDE) who fulfilled the criteria of either BD or MDD at inclusion. The discovery and replication cohorts consisted of 462 and 133 patients respectively. Patients were clinically assessed using standard diagnostic interviews, and clinical variables including current treatments were recorded. Blood was collected and serum assessed for levels of 31 cytokines using a sensitive multiplex assay. A penalized logistic regression model combined with nonparametric bootstrap was subsequently used to identify cytokines associated with BD. Interleukin (IL)-6, IL-10, IL-15, IL-27 and C-X-C ligand chemokine (CXCL)-10 were positively associated with BD in the discovery cohort. Of the five cytokines identified as discriminant features in the discovery cohort, IL-10, IL-15 and IL-27 were also positively associated with BD in the replication cohort therefore providing an external validation to our finding. Should our results be validated in a prospective cohort, they could provide new insights into the pathophysiological mechanisms of mood disorders.
Objectives
To provide a succinct, clinically useful summary of the management of bipolar disorder, based on the 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (MDcpg²⁰²⁰).
Methods
To develop the MDcpg²⁰²⁰, the mood disorders committee conducted an extensive review of the available literature to develop evidence‐based recommendations (EBR) based on National Health and Medical Research Council (NHMRC) guidelines. In the MDcpg2020, these recommendations sit alongside consensus‐based recommendations (CBR) that were derived from extensive deliberations of the mood disorders committee, who drew on their expertise and clinical experience. Therefore, this guideline summary is an abridged version that focuses on bipolar disorder. In collaboration with international experts in the field, it synthesises the key recommendations made in relation to the diagnosis and management of bipolar disorder.
Results
The bipolar disorder summary provides a systematic approach to diagnosis, and a logical clinical framework for management. It addresses the acute phases of bipolar disorder (mania, depression and mixed states) and its longer‐term management (maintenance and prophylaxis). For each phase it begins with Actions, which include important strategies that should be implemented from the outset wherever possible. These include for example, lifestyle changes, psychoeducation and psychological interventions. In each phase, the summary advocates the use of Choice medications for pharmacotherapy, which are then used in combinations along with additional Alternatives to manage acute symptoms or maintain mood stability and provide prophylaxis. The summary also recommends the use of ECT for each of the acute phases but not for maintenance therapy. Finally, it briefly considers bipolar disorder in children and its overlap in adults with borderline personality disorder.
Conclusions
The bipolar disorder summary provides up to date guidance regarding the management of bipolar disorder, as set out in the MDcpg²⁰²⁰. The recommendations are informed by evidence and clinical expertise and experience. The summary is intended for use by psychiatrists, psychologists and primary care physicians but will be of interest to anyone involved in the management of patients with bipolar disorder.
• The efficacy of lithium carbonate plus imipramine hydrochloride vs lithium carbonate plus placebo in preventing relapse was assessed in a prospective, hydro- doubleblind study of 75 bipolar 1 patients. Outcome measures included type of relapse, time until relapse, and subsequent illness course. Infrequent depressive relapse in either treatment group precluded any demonstration of an advantage of adding imipramine to a lithium carbonate regimen. There was little evidence that the combination of lithium carbonate and imipramine caused adverse reactions. However, interactions between type of most recent episode, treatment condition, sex, and type of relapse showed that women and mania-prone patients treated with imipramine had an increased risk of mania. Life table analysis showed that the overall probability of remaining well was the same for both treatment groups and that two thirds of all relapses occurred in the first six months.
Affective psychoses have distinctive phenomenology which is different from that for schizophrenia. The delusional and hallucinatory experiences in a 'pure' affective psychosis can usually be explained by the pathological mood and associated disturbances. Psychotic affective disorder is severe affective disorder, not schizophrenia, and in the authors' experience should be preferentially treated with antidepressant drugs or lithium salts; because of the severity of the disorder, higher than usual doses of these drugs and a longer than usual period of trial are recommended. In addition to affectively based delusional and hallucinatory experiences, patients suffering from affective illness also have what on cursory mental status examination may mimic 'schizophrenic' symptoms. The authors presented evidence to the effect that such situations are often caused by underlying or superimposed conditions that give rise to transient and epiphenomenal psychotic experiences of a nonaffective nature. Finally, even when such concurrent conditions cannot be demonstrated, the occasional and fleeting presence of Schneiderian symptoms or Bleulerian signs does not necessarily mean that an otherwise 'classical' affective psychosis should be reclassified under a 'schizoaffective' or 'schizophrenic' disorder; the overall clinical course of the psychotic episode-rather than cross-sectional mental status findings - should dictate the episode - rather diagnosis in such cases (along with the nature of past and future episodes, family history, and response to treatment). There are few, if any, pathognomonic diagnosis signs and symptoms in psychiatry. Therefore, the differential diagnosis of schizophrenic and affective psychoses cannot, and should not, be based on an occasional Bleurian sign or a Schneiderian symptom.
• Present clinical and research methods of differential diagnosis of schizophrenia and affective psychoses rely very heavily on presenting symptoms and signs, especially in acute psychosis. We have reviewed studies bearing on this issue, including studies of the phenomenology of psychotic illness, outcome, family history, response to treatment with lithium carbonate, and cross-national and historical diagnostic comparisons. We conclude that most so-called schizophrenic symptoms, taken alone and in cross section, have remarkably little, if any, demonstrated validity in determining diagnosis, prognosis, or treatment response in psychosis. In the United States, particularly, overreliance on such symptoms alone results in overdiagnosis of schizophrenia and underdiagnosis of affective illnesses, particularly mania. This compromises both clinical treatment and research.
Present clinical and research methods of differential diagnosis of schizophrenia and affective psychoses rely very heavily on presenting symptoms and signs, especially in acute psychosis. We have reviewed studies bearing on this issue, including studies of the phenomenology of psychotic illness, outcome, family history, response to treatment with lithium carbonate, and cross-national and historical diagnostic comparisons. We conclude that most so-called schizophrenic symptoms, taken alone and in cross section, have remarkably little, if any, demonstrated validity in determining diagnosis, prognosis, or treatment response in psychosis. In the United States, particularly, overreliance on such symptoms alone results in overdiagnosis of schizophrenia and underdiagnosis of affective illnesses, particularly mania. This compromises both clinical treatment and research.
Several investigators have recently challenged the belief that antidepressants can precipitate mania or rapid cycling between mania and depression. With one exception, there appear to be no placebo-controlled studies of switches into mania in bipolar patients during antidepressant treatment. Patients most likely to switch into mania during antidepressant therapy have probably been excluded from maintenance treatment studies and are probably overrepresented in studies at special research facilities. On balance, the available evidence suggests that some bipolar patients become manic, and a few experience rapid cycling, when they are treated with antidepressants. The prevention of these responses will require further research on risk factors and on the antimanic efficacy of coadministered lithium or other mood stabilizers.
Two studies were conducted to examine the viability of the major alternative models of the classification of schizoaffective disorder: that it is a subtype of schizophrenia, a type of affective disorder, on a continuum between schizophrenia and affective disorder, a totally independent disorder, or a heterogeneous category. The methodologies, taken from the prototype view of classification in cognitive psychology, study the behavior of the classifiers, in this case, clinicians assigning psychiatric diagnoses. These paradigms are especially useful in the study of schizoaffective disorder since different definitions of this diagnosis have resulted in widely discrepant findings. Therefore, finding the concept of schizoaffective disorder with the highest consensus is a reasonable first step before conducting empirical studies of patients. The first study attempted to locate exemplars or typical schizoaffective cases based on high diagnostic agreement and fast diagnostic decision time. Twenty clinicians assigned diagnoses to 30 cases, including 15 schizoaffective cases from the literature. While 11 exemplars were found for other diagnoses, only one was found for schizoaffective disorder. Schizoaffective cases were most often diagnosed as schizophrenia, particularly by more experienced clinicians. In the second study, 20 clinicians listed the essential clinical features of schizoaffective disorder and other major psychoses. The schizoaffective list shared as many features with schizophrenia as did the schizophrenic subtypes, but shared only one feature with the affective disorders. Overall, the results suggested that these clinicians perceive schizoaffective disorder as a variant of schizophrenia; however, this view of schizoaffective disorder may be changing in newer clinicians. Implications for defining schizoaffective disorder, suggestions for diagnosis, the generalizability of these findings and directions for future research are discussed.
The course of 434 bipolar patients (256 women, 178 men) was studied longitudinally. The prevailing patterns of the manic-depressive cycles at the end of the observation time were: mania followed by depression (usually mild), 28%; depression followed by mania (usually hypomania), 25%; and continuous circular course, with long cycles, 19%, or with short (rapid) cycles, 20%. The cycles followed an irregular pattern in 8% of the patients.
As to the intensity of the episodes, 52% of the patients had severe depressions and hypomanias; 26% had severe manias and mild depressions; and 22% had severe depressions and severe manias. No significant sex differences was found regarding the patterns of the cycles or the intensity of the episodes, except among the rapid cyclers, where women (61) outnumbered men (26).
With time the course tended to change from monopolar to bipolar, and the frequency of recurrence increased. Concurrent treatments, especially antidepressants, contributed to these changes, while female sex, middle age and menopause, along with antidepressant drugs, contributed to the establishment of rapid cyclicity. The depression-hypomania course was the one which was most prone to rapid cyclicity.
Response to lithium prophylaxis was good in the maniadepression-free interval course, in the continuous circular course with long cycles, and in the irregular course. It was less good in the depression-mania-free interval course, where it increased the frequency of recurrences, although these were shorter and milder. Response was very poor in the rapid cycling course. But rapid cyclers and patients with the depressionmania-free interval course responded well to lithium when antidepressant drugs were not administered during the depressions.
The efficacy of lithium carbonate plus imipramine hydrochloride vs lithium carbonate plus placebo in preventing relapse was assessed in a prospective, random-assignment double-blind study of 75 bipolar 1 patients. Outcome measures included type of relapse, time until relapse, and subsequent illness course. Infrequent depression relapse in either treatment group precluded any demonstration of an advantage of adding imipramine to a lithium carbonate regimen. There was little evidence that the combination of lithium carbonate and imipramine caused adverse reactions. However, interactions between type of most recent episode, treatment condition, sex, and type of relapse showed that women and mania-prone patients treated with imipramine had an increased risk of mania. Life table analysis showed that the overall probability of remaining well was the same for both treatment groups and that two thirds of all relapses occurred in the first six months.
One thousand five hundred and seventy eight first degree relatives of schizophrenics, manics, depressives and controls were personally interviewed using the Iowa Structured Psychiatric Interview Form without knowledge of the probands' diagnoses. Our data, based on blind diagnostic assessment of the relatives, support the distinction between schizophrenia and affective disorders, although the distinction between schizophrenia and mania was not clear-cut. Our data could not support familial subtyping of paranoid and non-paranoid schizophrenia, and unipolar and bipolar affective disorders. Future studies attempting to develop research criteria for subtyping schizophrenia and effective disorders should utilize not only clinical and familial data but also biological markers and other non-familial variables.
Risperidone is a new-generation atypical antipsychotic agent with potent dopaminergic and serotonergic antagonist activity. Compared with traditional dopamine-blocking neuroleptics, risperidone is more effective in treating negative symptoms of schizophrenia and may be less likely to cause extrapyramidal symptoms or tardive dyskinesia. Although risperidone is marketed for the treatment of schizophrenia, its novel psychopharmacologic effects and potentially mild side effect profile suggest the possibility of other therapeutic applications. An open prospective study was undertaken to determine whether risperidone might diminish psychosis, severe agitation, or rapid cycling in patients having acute and chronic primary affective illnesses (bipolar and major depressive disorder) and to document response characteristics and side effects. Additionally, a small number of patients with refractory obsessive-compulsive disorder (OCD) without comorbid tic or delusional disorders were given open trials of risperidone added to their medication.
Outpatients who fulfilled DSM-IV criteria for bipolar I, bipolar II, or major depressive disorder and suffered from psychosis or agitation associated with their illness (N = 20) and those who had treatment-refractory DSM-IV OCD (N = 5) were started on open trials of risperidone at daily doses of 1 to 1.5 mg. Doses were adjusted upwards to a maximum of 6 mg depending on clinical response.
Seventeen (85%) of 20 patients (13 bipolar, 4 major depressive disorder) showed complete or partial improvement after treatment with risperidone doses ranging from 1 to 6 mg/day (mean = 3.5 mg). Beneficial effects included decreases in agitation, psychosis, sleep disturbance, and rapid cycling. Four patients (20%) discontinued risperidone because of intolerable side effects. Five patients with refractory OCD also showed significant symptomatic improvement after the addition of risperidone.
The findings suggest that (1) risperidone may be useful in the acute/p.r.n. and chronic treatment of psychosis, agitation, and cycling accompanying affective illness, and (2) risperidone may be useful in augmenting pharmacologic response in OCD.
This study examined the clinical correlates of lack of insight in bipolar disorder. In 28 acutely manic patients interviewed upon hospitalization and/or discharge, mean scores on the Insight and Treatment Attitudes Questionnaire (ITAQ) improved only slightly, from 12.0 on admission to 15.5 on discharge (p = .08), despite marked improvement in other psychiatric symptoms. A reciprocal relationship was found between higher ITAQ scores and involuntary hospitalization (r = -.38). Like schizophrenia, bipolar disorder appears to be a condition in which poor insight is a prominent characteristic.
The longitudinal course of 51 patients with treatment-refractory bipolar disorder was examined to assess possible effects of heterocyclic antidepressants on occurrence of manic episodes and cycle acceleration.
Using criteria established from life charts, investigators rated the patients' episodes of mania or cycle acceleration as likely or unlikely to have been induced by antidepressant therapy. Discriminant function analyses were performed to assess predictors of vulnerability to antidepressant-induced mania or cycle acceleration. Further, the likelihood of future antidepressant-induced episodes in persons who had had one such episode was assessed.
Thirty-five percent of the patients had a manic episode rated as likely to have been antidepressant-induced. No variable was a predictor of vulnerability to antidepressant-induced mania. Cycle acceleration was likely to be associated with antidepressant treatment in 26% of the patients assessed. Younger age at first treatment was a predictor of vulnerability to antidepressant-induced cycle acceleration. Forty-six percent of patients with antidepressant-induced mania, but only 14% of those without, also showed antidepressant-induced cycle acceleration at some point in their illness.
Mania is likely to be antidepressant-induced and not attributable to the expected course of illness in one-third of treatment-refractory bipolar patients, and rapid cycling is induced in one-fourth. Antidepressant-induced mania may be a marker for increased vulnerability to antidepressant-induced cycle acceleration. Antidepressant-induced cycle acceleration (but not antidepressant-induced mania) is associated with younger age at first treatment and may be more likely to occur in women and in bipolar II patients.
The significant prevalence of substance use disorders among patients with psychiatric illnesses has attracted increasing interest. One large epidemiologic study indicates that, of all Axis I disorders, bipolar disorder is the most likely to co-occur with alcohol or drug abuse. Evidence is emerging that shows that bipolar patients who also abuse drugs or alcohol have an earlier onset and worse course of illness compared with those who do not. They are more likely to experience irritable and dysphoric mood states, increased treatment resistance, and a greater need for hospitalization. Caution about diagnosing bipolar disorder in the presence of substance abuse is advised because of overlapping symptomatology. A rationale for the pharmacologic approach to treatment is explored. Data from several studies indicate that the presence of a substance use disorder may be a predictor of poor response to lithium. While it is possible that the anticonvulsants divalproex sodium and carbamazepine may be more useful in this population, a direct comparison of lithium with the anticonvulsants in a substance-abusing population of individuals with bipolar disorder has not yet been performed. Further investigation of diagnostic and treatment issues in this important population of patients with bipolar disorder is needed.
Although treatment of bipolar depression is a frequent clinical problem, double-blind studies of the treatment of bipolar depression are scarce. Some case series and uncontrolled data suggest antidepressants may differ in their propensity to induce mania or their efficacy for bipolar depression.
The authors conducted a prospective double-blind trial to assess efficacy and rate of treatment-emergent mood elevation in depressed bipolar patients when bupropion or desipramine was added to an ongoing therapeutic regimen of lithium or an anticonvulsant. Results were assessed after 8 weeks of acute treatment and during maintenance treatment up to 1 year.
No difference was found for acute efficacy between the two drugs. Mania/hypomania was observed in 5 of 10 desipramine-treated patients, but only 1 of 9 bupropion-treated patients. The occurrence of hypomania or mania was correlated with treatment group (Kendall's tau correlation = 0.42; Z = -2.5, p < .012).
These pilot findings suggest that bupropion is less likely to induce mood elevation than desipramine. For treatment of bipolar depression, bupropion and desipramine appear to have similar antidepressant efficacy.
This study tested the impression that there have been significant shifts in the relative diagnostic frequencies of schizophrenia and major affective disorders.
Data on discharge diagnoses from 1972 to 1988 were gathered from six North American psychiatric teaching hospitals (data from one extended through 1991), and rates for schizophrenia and major mood disorders were evaluated.
Total annual discharges increased by 6.6% during the study period. Large reciprocal shifts in the frequencies of diagnoses of schizophrenia and major affective disorders were found; schizoaffective disorder was a minor diagnosis. Beginning in the early 1970s, a gradual increase in the frequency of diagnoses of major affective disorders at all sites was accompanied by a corresponding decrease in diagnoses of schizophrenia at five of the six centers. Schizophrenia diagnoses decreased from a peak of 27% in 1976 to 9% in 1989 (a threefold decrease), and diagnoses of major affective disorders rose from a low of 10% in 1972 to 44% in 1990 (a fourfold increase).
Several forces may have influenced these changes. 1) DSM-III narrowed the definition of schizophrenia and broadened the category of major affective disorders. 2) Treatment-oriented diagnostic bias associated with the availability of lithium and other mood-altering agents may have encouraged consideration of affective disorders. 3) Economic and social forces, including better third-party reimbursement rates, may have favored affective diagnoses. 4) True increases in the incidence of affective disorders may have occurred. 5) Although a real decrease in new cases of schizophrenia may have occurred, this effect was probably minor and dominated by a larger shift of such diagnoses to affective categories.
Based on the author's work and that of collaborators, as well as other contemporaneous research, this article reaffirms the existence of a broad bipolar spectrum between the extremes of psychotic manic-depressive illness and strictly defined unipolar depression. The alternation of mania and melancholia beginning in the juvenile years is one of the most classic descriptions in clinical medicine that has come to us from Greco-Roman times. French alienists in the middle of the nineteenth century and Kraepelin at the turn of that century formalized it into manic-depressive psychosis. In the pre-DSM-III era during the 1960s and 1970s, North American psychiatrists rarely diagnosed the psychotic forms of the disease; now, there is greater recognition that most excited psychoses with a biphasic course, including many with schizo-affective features, belong to the bipolar spectrum. Current data also support Kraepelin's delineation of mixed states, which frequently take on psychotic proportions. However, full syndromal intertwining of depressive and manic states into dysphoric or mixed mania--as emphasized in DSM-IV--is relatively uncommon; depressive symptoms in the midst of mania are more representative of mixed states. DSM-IV also does not formally recognize hypomanic symptomatology that intrudes into major depressive episodes and gives rise to agitated depressive and/or anxious, dysphoric, restless depressions with flight of ideas. Many of these mixed depressive states arise within the setting of an attenuated bipolar spectrum characterized by major depressive episodes and soft signs of bipolarity. DSM-IV conventions are most explicit for the bipolar II subtype with major depressive and clear-cut spontaneous hypomanic episodes; temperamental cyclothymia and hyperthymia receive insufficient recognition as potential factors that could lead to switching from depression to bipolar I disorder and, in vulnerable subjects, to predominantly depressive cycling. In the main, rapid-cycling and mixed states are distinct. Nonetheless, there exist ultrarapid-cycling forms where morose, labile moods with irritable, mixed features constitute patients' habitual self and, for that reason, are often mistaken for "borderline" personality disorder. Clearly, more formal research needs to be conducted in this temperamental interface between more classic bipolar and unipolar disorders. The clinical stakes, however, are such that a narrow concept of bipolar disorder would deprive many patients with lifelong temperamental dysregulation and depressive episodes of the benefits of mood-regulating agents.
The chronic, complex, and episodic course of bipolar mood disorder presents a formidable challenge to the clinician making a treatment plan. Although numerous therapeutic agents are reported to be efficacious for one or more aspects of bipolar illness, treatment is seldom completely effective and is never curative. The goal of treatment is to modify the symptomatic expression of the illness with the result that fewer, briefer, and milder episodes occur. In pursuit of this goal, the use of multiple medications, polypharmacy, is the rule rather than the exception. This article offers recommendations for treatment strategies based on the phase and stage of the illness. The strategies are organized into algorithms that emphasize the use of mood-stabilizing medications as initial steps in a systematic, iterative approach to treatment. Practical issues related to the use of mood-stabilizing therapies are discussed.
Iis often difficult to establish whether certain patients should he given the diagnosis of bipolar disorder, borderline personality disorder, or both. This case high- lights how knowledgeable psychi- atnists can have contrasting diag- nostic views about patients with volatile moods and impulsivity and how such disagreement can create problems in providing effective treatment. The patient described in this case report conceptualized her psychiatric problem as due to hipo- lan disorder, which she was told meant a biochemical illness charac- tenized by mood swings not under her control. She was told that this genetically determined disease could he stabilized by using the proper combination of medica- tions. This conceptualization of her illness sharply contrasted with the diagnosis developed during consul- tation-horderline personality dis- order. At that point the patient was told that she suffered from a psy- chiatnic disorder caused by devel- opmental difficulties that are best treated by psychosocial treatments, with psychopharmacology as an adjunctive treatment. With this di- agnosis she was expected to in- creasingly take responsibility for managing her mood swings and im-
The objective of the current study was to better understand the nature of prodromal and residual symptoms of mania and depression, as reported by patients with bipolar I disorder and their family members. Prodromal and residual symptoms of mania and depression were elicited from 74 patients with bipolar I disorder. In 45 cases, an adult family member provided similar information. Three clinicians classified the symptoms into six broad categories: behavioral, cognitive, mood, neurovegetative, social, and other. The clinicians also categorized symptoms as typical or idiosyncratic. Seventy-eight percent of the patients reported prodromal depressive symptoms and 87% reported prodromal manic symptoms; greater than half of the patients disclosed residual symptoms of depression (54%) and mania (68%). Within each of these four illness categories, cognitive symptoms were consistently the most common symptoms reported by patients. A substantial number of symptoms were idiosyncratic, particularly those reported for residual depression. Agreement between patient and family members on reported symptoms was strong for the prodromal phase of both polarities, but less so for the residual phases. These preliminary results suggest that patients with bipolar I disorder and their family members can identify prodromal and residual symptoms, that these symptoms are quite common, and that prodromal symptoms may be more prevalent or easier to identify than residual symptoms. Cognitive symptoms were consistently the most common symptoms reported by patients.
Thirty-three outpatients who met DSM-IV criteria for major depressive disorder (MDD) with no history of manic or hypomanic symptomatology were enrolled in an 8-week open trial of valproate. By Week 4, 15 of the 28 completers (54%) demonstrated a significant clinical response as defined by a score reduction of 50 percent or more or a total score of 9 or lower on the Hamilton Rating Scale for Depression (HRSD). Mean HRSD scores of the completers decreased 48.8 percent at Week 4 (p < .0001). At Week 8, 19 of the 22 completers (86%) showed a significant response. Mean HRSD scores decreased from 22 +/- 5 at baseline to 7 +/- 4 at Week 8 (p < .0001). With the intent-to-treat analysis at Week 8, 66 percent were responders, and total group mean HRSD scores decreased 55 percent (p < .0001). The data suggest that valproate may be an effective treatment for MDD. Double-blind, placebo-controlled trials are needed to further document its efficacy in the treatment of MDD.
To test the hypothesis that, although typical neuroleptics are commonly used in the treatment of bipolar disorder, newer atypical antipsychotic agents, like risperidone, may be more effective and better-tolerated.
The effectiveness of risperidone was evaluated in 14 outpatients with bipolar disorder, type I, who received risperidone for 6.4 +/- 2.7 weeks at 2.75 +/- 1.8 mg/day.
Nine (64%) patients were much improved based on Clinical Global Impression (CGI) scores, and mean Global Assessment of Functioning (GAF) scores improved from 48.2 +/- 4.9 to 58.8 +/- 7.3 (t = 4.49, P = 0.0006, paired t test). Treatment was well tolerated, and no patient experienced worsening of mood symptoms while receiving risperidone.
This open series suggests risperidone is beneficial in the treatment of outpatients with bipolar disorder.
This pilot study compared the efficacy of lithium plus divalproex sodium with the efficacy of lithium alone for the continuation and maintenance treatment of patients with bipolar I disorder.
Twelve patients with bipolar I disorder as defined by the DSM-III-R were recruited and followed prospectively for up to 1 year. Each subject received lithium at serum levels of 0.8 to 1.0 mmol/L and a management/education session weekly or every 2 weeks. By random assignment, subjects received either divalproex sodium or placebo in conjunction with lithium. Divalproex sodium was adjusted to achieve a serum concentration of 50 to 125 micrograms/mL. Adjunctive medications were used on an as needed basis to treat psychosis, depression, and anxiety. The course of illness was monitored through use of the Longitudinal Interval Follow-up Examination.
Subjects treated with the combination of lithium and divalproex were significantly less likely to suffer a relapse or recurrence (p = .014), but were significantly more likely to suffer at least one moderate or severe adverse side effect (p = .041). There was no significant difference between groups in the use of adjunctive medication.
These results provide preliminary evidence of the risks and benefits of combining lithium with divalproex sodium for the continuation and maintenance treatment of bipolar I disorder.
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Sequence of agents in stages II and Psychotic forms of depres-III is not yet definitively established based on the sion and mania
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A pilot study of lithium etine and imipramine in the treatment of bipolar depression, carbonate plus divalproex sodium for the continuation and 2nd International Conference on Bipolar Disorder. Pittsburgh. maintenance treatment of patients with bipolar I disorder
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Lack of insight in this algorithm at stages II or III in the near future. bipolar disorder
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National survey of NDMDA members finds current data available. Stage IV may be moved up to long delay in diagnosis of manic-depressive illness
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A double-blind placebo-controlled trial comparing the effect of paroxetine and imipramine in the treatment of bipolar depression
- M L Young
- C D Pitts
- R Oakes
- I P Gergel
Risperidone in the treatment of mania
- M Tohen
- C A Zarate
- F Centorrino
- J Hegary
- M Froeschl
- M Weiss
- R J Baldessarini