A consecutive series of treated affected offspring of parents with bipolar disorder: is response associated with the clinical profile?

OBJECTIVE: In adults with established bipolar disorder (BD), differential response to mood stabilizers has been associated with the clinical profile. Long-term treatment studies of youth with BD are lacking. This paper provides longitudinal observations of response to mood stabilizers early in the course of illness in youth with BD. METHOD: We report on 15 research patients who, as adolescents, met DSM-IV lifetime criteria for a bipolar spectrum disorder and required long-term treatment. These youths derived from families with one parent having BD whose course and long-term treatment response were determined in accordance with research criteria. The patients were offered lithium, and if they failed to respond or refused it, they were treated with either an anticonvulsant or an atypical antipsychotic. Using a validated scale, an independent rater retrospectively blindly scored the response to long-term treatment. RESULTS: Those patients who stabilized on lithium derived from lithium-responsive families, whereas those who stabilized on an antipsychotic derived from lithium-nonresponsive families. The clinical course in the youths stabilized by lithium differed from that in the youths stabilized by an atypical antipsychotic. CONCLUSIONS: Our findings suggest that the clinical profile may help in selecting effective stabilizing treatment and that a proportion of youth can be stabilized on monotherapy. This is a small case series with nonrandom treatment assignment, and the findings should be considered tentative.     

Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children.

BACKGROUND: Controversy concerning the diagnosis of pediatric bipolar disorder (BD) has focused attention on children with chronic irritability and hyperarousal. This syndrome has been called the "broad BD phenotype" or severe mood dysregulation (SMD). This study examines prevalence, concurrent Axis I diagnoses, and longitudinal outcome of SMD in an epidemiologic sample. METHODS: Data were drawn from the Great Smoky Mountains Study, a longitudinal epidemiological study. Items from the Child and Adolescent Psychiatric Assessment were used to generate SMD criteria. RESULTS: Among 1420 children, the lifetime prevalence of SMD in children ages 9-19 was 3.3%. Most (67.7%) SMD youth had an Axis I diagnosis, most commonly attention-deficit/hyperactivity disorder (26.9%), conduct disorder (25.9%), and/or oppositional defiant disorder (24.5%). In young adulthood (mean age 18.3 +/- 2.1 years), youth who met criteria for SMD in the first wave (mean age 10.6 +/- 1.4 years) were significantly more likely to be diagnosed with a depressive disorder (odds ratio 7.2, confidence interval 1.3-38.8, p = .02) than youth who never met criteria for SMD. CONCLUSIONS: Severe mood dysregulation is relatively common in childhood and predicts risk for early adulthood depressive disorders. Research should continue to explore the course of illness in children with SMD.     

Diagnosis and treatment of chronic depression in children and adolescents

Chronic unipolar depression is being increasingly recognized in general psychiatry as a particularly severe form of depressive illness that leads to significant symptomatology, prolonged suffering, and prolonged functional impairment in a variety of domains, including educational/vocational dysfunction as well as interpersonal impairment. Recent research on treatment interventions for adult patients with chronic depressions suggests that standard treatments for depressive illness may need modification to benefit patients with chronic illness. Little attention at this point has been given to the problem of chronic depression in children and adolescents. Many adults with chronic depressive disorders had onset of depression in their childhood or adolescence, making early identification of this form of illness a priority. The authors present a comprehensive review of emerging literature in the assessment, clinical course, and treatment of chronic forms of unipolar depression in youth. They then develop summary recommendations for the assessment and treatment of this type of mood disorder in youth, based on the currently available research and common sense clinical experience.     

Neural correlates of cognitive flexibility in children at risk for bipolar disorder

BackgroundYouth with bipolar disorder (BD) show behavioral and neural deficits in cognitive flexibility; however, whether such deficits exist among youths at risk for BD has not been explored.MethodsThe current fMRI study examined the neural basis of cognitive flexibility in BD youth (n = 28), unaffected youth at risk for BD (AR; n = 13), and healthy volunteer youth (HV; n = 21) by comparing brain activation patterns while participants performed the change task. On change trials, subjects must inhibit a prepotent response and execute an alternate one.ResultsDuring successful change trials, both BD and AR youth had increased right ventrolateral prefrontal and inferior parietal activity, compared to HV youth. During failed change trials, both BD and AR youth exhibited increased caudate activation relative to HV youth, but BD youth showed increased activation in the subgenual anterior cingulate cortex (ACC) relative to the other two groups.ConclusionsAbnormal activity in ventrolateral prefrontal cortex, inferior parietal cortex, and striatum during a cognitive flexibility task may represent a potential BD endophenotype, but subgenual ACC dysfunction may represent a marker of BD illness itself.     

Neurocognitive Functioning in Overweight and Obese Patients With Bipolar Disorder: Data From the Systematic Treatment Optimization Program for Early Mania (STOP-EM)

Objective

Obesity is frequent in people with bipolar I disorder (BD I) and has a major impact on the course of the illness. Although obesity negatively influences cognitive function in patients with BD, its impact in the early phase of the disorder is unknown. We investigated the impact of overweight and obesity on cognitive functioning in clinically stable patients with BD recently recovered from their first manic episode.

Method:

Sixty-five patients with BD (25 overweight or obese and 40 normal weight) recently remitted from a first episode of mania and 37 age- and sex-matched healthy control subjects (9 overweight or obese and 28 normal weight) were included in this analysis from the Systematic Treatment Optimization Program for Early Mania (commonly referred to as STOP-EM). All subjects had their cognitive function assessed using a standard neurocognitive battery. We compared cognitive function between normal weight patients, overweight–obese patients, and normal weight healthy control subjects.

Results:

There was a negative affect of BD diagnosis on the domains of attention, verbal memory, nonverbal memory, working memory, and executive function, but we were unable to find an additional effect of weight on cognitive functioning in patients. There was a trend for a negative correlation between body mass index and nonverbal memory in the patient group.

Conclusions:

These data suggest that overweight–obesity does not negatively influence cognitive function early in the course of BD. Given that there is evidence for a negative impact of obesity later in the course of illness, there may be an opportunity to address obesity early in the course of BD.     

Increased anterior cingulate cortex volume in bipolar I disorder

OBJECTIVE: Functional neuroimaging studies have implicated the anterior cingulate cortex (ACC) in the pathophysiology of bipolar disorder (BD), but findings from volumetric studies have been less consistent, therefore the purpose of the present study was to further investigate the existence of volumetric abnormalities in the ACC cortex of individuals with BD. In addition to methodological inconsistencies many previous studies have been lacking robustness clinically with respect to characterizing bipolar patients and comparison subjects. Hence, the present study matched the groups closely across a number of demographic parameters. METHODS: Using magnetic resonance imaging, ACC volumes of 24 bipolar patients were compared to 24 gender-, age-, and education-matched control subjects, and these findings were further investigated in relation to both illness and treatment factors. RESULTS: A significantly larger (26%) right ACC in bipolar patients than control subjects was seen, and this difference was not associated with a history of psychosis, familiality, or lithium treatment, after controlling for potential confounds. Patients reporting fewer affective episodes did, however, have significantly larger ACC volumes than controls, suggesting ACC volumetric changes early in the course of BD. CONCLUSIONS: An increase in the size of the ACC may have important implications for the neurobiology of BD. It is suggested that attempts to control affective instability during the early stages of the illness necessitates greater ACC mediation via its role in conflict resolution and hence this is reflected in the increased size of the ACC early in the course of the illness.     

Psychiatric response to HIV spectrum disease in children and adolescents

Five clinical situations involving children and adolescents exposed to human immunodeficiency virus illustrate the psychosocial spectrum of the disease. For at-risk gay youth, anxiety and stigma complicate developing sexual practices. Children with perinatal infection may survive for years with a chronic illness, management of which is complicated by parental illness or death. Hemophiliac families must deal with the intrusion of a lethal virus into a long illness course. "Street" adolescents and substance-abusing youth pose particular challenges to public health and education. The range of child psychiatric responses described includes individual and family therapy, neuropsychological assessment, psychopharmacological management, and consultation liaison work.     

A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder

BACKGROUND: Cognitive dysfunction is evident in some euthymic patients with established bipolar disorder (BD), including deficits in visual backward masking (VBM) tasks which map to a specific neural pathway. A high-risk paradigm would clarify the temporal relation of cognitive dysfunction to clinical course. METHOD: We compared euthymic offspring (age range: 18-32 years) of lithium-responsive bipolar parents with and without a previous lifetime history of psychiatric illness to healthy comparison subjects with a negative family history, on a VBM task that requires target location. RESULTS: High-risk offspring with no lifetime psychiatric history performed the VBM task at levels of healthy controls. High-risk offspring with a previous history of a mood disorder, in complete remission, made significantly more errors at short target-mask intervals than control or never ill offspring. These higher error rates were not a consequence of faster response times. CONCLUSIONS: There is preliminary evidence of specific cognitive dysfunction early in the course of illness in affected offspring of parents with lithium responsive BD. VBM is ideal for future longitudinal studies addressing whether cognitive dysfunction in BD is a trait marker or a consequence of illness manifestation.     

Characterization and Factors Associated with Sleep Quality in Adolescents with Bipolar I Disorder

Sleep disturbance is an early marker for bipolar disorder (BD) onset in youth. We characterized sleep quality in adolescents experiencing mania within the last 6-12 months. We examined the association between mood and sleep in 27 adolescents with BD and 24 matched healthy controls (HC). Subjects were assessed by parent and teen report of sleep, a semi-structured clinical interview, the Young Mania Rating Scale (YMRS), and the Childhood Depression Rating Scale (CDRS-R). Average BD youth YMRS (mean 20.3 ± 7.3) and CDRS-R (mean 42.4 ± 14.1) scores indicated they were still ill at time of assessment. Compared to HCs, adolescents with BD have distinct patterns of prolonged sleep onset latency, frequent nighttime awakenings, and increased total time awake. Mood symptoms, specifically excessive guilt, self-injurious behavior, and worsening evening mood, interfered with sleep. Further studies are needed to determine whether early regulation of sleep would improve long-term outcome in BD youth.     

Détection et intervention précoce auprès des jeunes avec trouble bipolaire émergent : où en sommes-nous ?

Bipolar disorder (BD) is one of the most disabling chronic illness for which the delay in diagnosis and access to adequate care is about 10 years, with many consequences such as numerous comorbidities, greater illness severity and resistance to treatments. Building on advances in early intervention in psychosis, optimizing the detection of patients with BD and intervening early is essential to improve their prognosis. Identifying risk factors for BD would allow earlier detection of the target population with the aims of: (1) preventing the development of the disease, (2) delaying its onset and (3) improving the course through more timely treatment. We conducted a narrative review of the literature of the past 30 years on risk factors of BD and synthetising the concepts of at-risk of BD mental state, the staging model and associated interventions. These concepts are illustrated by a clinical case with and without early intervention highlighting the challenges of early intervention in BD and the scientific data currently available of use to the clinician (both general practitioners and psychiatrist). In addition to genetic and environmental risk factors (early trauma, substance use, etc.), vulnerability markers (cyclothymic or hyperthymic temperament, cluster B personality disorder) can guide the clinician towards the detection of at risk of BD mental state syndrome consisting of attenuated symptoms of hypomania, mood lability, early depressive episode with psychotic, severe or atypical characteristics. The delay in access to care attributable to the absence of “help-seeking”, to self-stigmatization, or to unrecognized diagnoses (misdiagnosis with personality disorders or substance use disorders) weighs down the prognosis leading, as episodes cumulate over time, to incomplete remission of episodes with residual symptoms and significant functional decline. The use of validated tools and careful coordination of the various actors are assets for the early identification of subjects at-risk of transition to BD. Following the staging model, targeted primary prevention interventions (e.g., promotion of good sleep hygiene, stress management strategies) for at-risk individuals should be offered by general practitioner or other front-line mental health professionals (e.g., psychologist, nurse); early secondary prevention (for stage 1) should be provided by general psychiatric or general medicine services. Although no official guidelines for early intervention for BD are available yet, experts opinions are multiplying and supporting an integrated approach that maximizes young patient engagement. These integrated approaches aiming at symptomatic and functional improvement combine effective psychopharmacology and psychosocial interventions, including cognitive- behavioral therapy, approaches based on social rhythm, psychoeducation, relapse prevention, social and vocational recovery and family interventions. The scarcity of studies on the early stages of bipolar disorder limits the predictive value of risk factors and at-risk syndromes which remain to be validated. Prospective controlled studies are warranted to improve the prevention efforts and effective early treatment of bipolar disorder.     

Staging and Neuroprogression in Bipolar Disorder

The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression.     

Early Detection and Intervention in Bipolar Affective Disorder: Targeting the Development of the Disorder

The diagnosis of bipolar affective disorder (BD) is often delayed, and preceded by incorrect diagnoses and potentially harmful treatment, while the development of the disorder is associated with suicidal behavior and help seeking. Several clinical features have been linked to an increased risk of going on to develop BD, in particular attenuated symptoms of BD, personality traits such as cyclothymia, and general psychopathologic symptoms. Several of these show high specificity, indicating that it may be possible to target detection and intervention in individuals at high risk of BD and perhaps moderate the course of the illness and improve treatment outcome. This article summarizes recent evidence on the characteristics of the prodrome to BD and discusses the potential value and challenges of early detection and intervention in BD.     

Early age at onset of bipolar disorder is associated with more severe clinical features but delayed treatment seeking

OBJECTIVE: Our aim was to obtain a comprehensive view of differences between bipolar disorder (BD) patients with onset at early versus adult age in a representative study cohort. METHODS: In the Jorvi Bipolar Study (JoBS), 1,630 psychiatric in- and outpatients were systematically screened for BD using the Mood Disorder Questionnaire (MDQ). A total of 191 bipolar I and II patients with a current DSM-IV episode were interviewed to obtain information about age at onset of mood symptoms, clinical course, treatment, comorbidity, and functional status. The patients were classified as either early onset (<18 years) or adult onset. RESULTS: One-third of subjects with BD (58/191, 30%) had early onset. This was associated with female gender, more lifetime psychotic symptoms, greater overall comorbidity, and a greater length of time from first episode to treatment. CONCLUSIONS: Although BD patients with early age at onset have more severe clinical features and illness course, the delays from first episode to treatment and to correct diagnosis are longer than for those with adult onset disorder. To reduce morbidity rates related to the most severe forms of BD, the recognition and diagnosis of BD during adolescence needs to be improved.     

Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder

BACKGROUND: The purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bipolar disorder (BD). Previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with BD have been inconsistent in their findings and limited to adult samples. Appreciation of whether volumetric abnormalities are early features of BD or whether the abnormalities represent neurodegenerative changes associated with illness duration is limited by the paucity of data in juvenile samples. OBJECTIVE: To investigate amygdala and hippocampal volume in adults and adolescents with BD.Setting and PARTICIPANTS: Subjects included 36 individuals (14 adolescents and 22 adults) in outpatient treatment for BD type I at a university hospital or Veterans Affairs medical center or in the surrounding community, and 56 healthy comparison subjects (23 adolescents and 33 adults).Design and MAIN OUTCOME MEASURES: Amygdala and hippocampal volumes were defined and measured on high-resolution anatomic magnetic resonance imaging scans. We used a mixed-model, repeated-measures statistical analysis to compare amygdala and hippocampal volumes across groups while covarying for total brain volume, age, and sex. Potential effects of illness features were explored, including rapid cycling, medication, alcohol or other substance dependence, duration, and mood state. RESULTS: For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P<.0001). Amygdala volume reductions (15.6%) were highly significant (P<.0001). We observed a nonsignificant trend (P =.054) toward reductions in hippocampal volumes of lesser magnitude (5.3%). Effects of illness features were not detected. CONCLUSIONS: These results suggest that BD is associated with decreased volumes of medial temporal lobe structures, with greater effect sizes in the amygdala than in the hippocampus. These abnormalities are likely manifested early in the course of illness, as they affected adolescent and adult subjects similarly in this sample.     

Risk factors associated with childbearing-related episodes in women with bipolar disorder

OBJECTIVE: For the onset of illness and possible recurrence during the childbearing period, women with bipolar disorder (BD) are at a higher risk. The aim of this study was to evaluate the impact of clinical and psychosocial factors associated with pregnancy and the postpartum period on the course of BD. METHODS: The childbearing and illness history of 72 women with BD were assessed to determine mood episodes related to the childbearing period. Data was analyzed to evaluate the risk factors (clinical, obstetric and psychosocial factors) related with mood episodes during pregnancy and the postpartum period. RESULTS: Data of 252 pregnancies and childbirths of 72 women with BD were included in the analysis. Twenty-three (32%) women with BD reported at least one mood episode during pregnancy or within 1 month after childbirth (childbearing-related episode, CBRE). Subjects with CBREs mean age at onset of illness and mean age at the time of assessment were significantly younger than subjects with N-CBRE. A lower number of women who experienced a postpartum episode after the birth of the first child chose to have the second one. Psychosocial factors during pregnancy and the postpartum period and method of delivery did not predict the first postpartum episode. Onset of illness at an early age, experiencing episode during the first pregnancy and experiencing physical problems during pregnancy predicted a mood episode during the first postpartum period. CONCLUSIONS: Interpretation of the results of the study is limited with the retrospective nature of data collection. Within the limitations, we may suggest that psychosocial factors do not play a significant role in the genesis of CBREs in women with BD.     

Population-Based Initiatives in College Mental Health: Students Helping Students to Overcome Obstacles

Bipolar disorder (BD) is a chronic psychiatric illness of which the etiology remains unknown. Extensive research has provided some hypotheses for the pathophysiology of this disorder; however, there are no molecular tests available to help support the diagnosis obtained by self-report and behavioral observations. A major requirement is to identify potential biomarkers that could be used for early diagnosis in patients susceptible to the disease and for its treatment. The most recently published findings regarding alterations in BD were found to be related to oxidative stress, inflammatory and trophic factor deregulation, and also polymorphisms of genes that are associated with the development of BD. Many of these targets are potential biomarkers which could help to identify the BD subgroups and to advance treatment strategies, which would beneficiate the quality of life of these patients. Therefore, the main objective of this review is to examine the recent findings and critically evaluate their potential as biomarkers for BD.     

In vivo evidence for early neurodevelopmental anomaly of the anterior cingulate cortex in bipolar disorder

Objective: Anterior cingulate cortex (ACC) abnormalities are commonly reported in studies of patients with bipolar disorder (BD), but it is unclear whether these precede or follow illness onset. We investigated the evidence for early neurodevelopmental anomalies in the ACC and adjacent paracingulate cortex (PaC) of BD patients by studying cortical folding patterns of the region. Method: Magnetic resonance images were acquired from 54 BD patients and 116 healthy controls. Cortical folding patterns were assessed by classifying the incidence of the paracingulate sulcus (PCS) and interruptions in the course of the cingulate sulcus (CS). Results: Patients were significantly less likely to show a PCS bilaterally. There were no differences in the frequency of CS interruptions. Conclusion: The bilateral reduction observed in our patient sample implicates aberrant pre‐ or peri‐natal developmental processes. To our knowledge, this is the first in vivo evidence for early neurodevelopmental anomaly of the ACC/PaC region in BD.     

重性抑郁障碍与双相障碍患者躯体疾病共病调查

目的:了解重性抑郁障碍(MDD)与双相障碍(BD)患者躯体疾病共病情况。方法:对141例MDD和52例BD患者进行一般情况、躯体疾病调查及精神疾病评估。结果:MDD和BD患者躯体疾病的共病率分别为68.1%、46.2%,共病的躯体疾病以慢性病为主,依次为高血压、慢性胃炎、腰椎间盘突出、糖尿病。与非共病患者比较,共病患者年龄及起病年龄大,精神疾病复发次数多(P0.05或P0.01)。MDD共病患者自杀意念风险明显增加(P0.01)。结论:较高龄及较高龄起病的MDD、BD患者更易共病慢性躯体疾病。     

Insulin-like Growth Factor 1 Differentially Affects Lithium Sensitivity of Lymphoblastoid Cell Lines from Lithium Responder and Non-responder Bipolar Disorder Patients

Journal of Molecular Neuroscience - Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about...     

Increased BDNF Levels in Long-term Bipolar Disorder Patients

IntroductionBipolar disorder (BD) is a prevalent, chronic and progressive illness. There is a growing body of evidence indicating that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of BD.ObjectiveThe aim of this study was to evaluate BDNF plasma levels in BD patients with long term illness in comparison with controls.Methods87 BD type I patients and 58 controls matched by age, gender and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatric Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of BDNF were measured by ELISA.ResultsOn average, patients had suffered from BD for 23.4 years. In comparison with controls, BD patients with mania presented a 1.90-fold increase in BDNF plasma levels (p = .001), while BD patients in remission presented a 1.64-fold increase in BDNF plasma levels (p = .03). BDNF plasma levels were not influenced by age, length of illness or current medications.ConclusionsThe present study suggests that long-term BD patients exhibit increased circulating levels of BDNF.