Neurochemical predictors of response to pharmacologic treatments for bipolar disorder

Bipolar disorder is a common psychiatric disorder that is characterized by recurrent episodes of mania and often depression. Mood stabilizers and antipsychotics are first-line pharmacologic options for patients with bipolar disorder. However, the exact mechanisms by which these medications exert the mood stabilizing effects are unknown. Additionally, individuals with bipolar disorder often try several medications unsuccessfully before achieving mood stabilization. Magnetic resonance spectroscopy (MRS) is a noninvasive neuroimaging technique that can be used to identify the neurochemical effects and predictors of response to medications commonly used to treat bipolar disorder. MRS may facilitate targeted treatment interventions and decrease the morbidity and mortality associated with this illness. Examining the mechanisms of action of pharmacologic agents used to treat bipolar disorder may clarify the neurophysiologic basis of bipolar disorder. We will review recent MRS investigations that have evaluated the neurochemical effects of pharmacologic treatments and predictors of treatment response in patients with bipolar disorder.     

Syndrome métabolique et troubles bipolaires : le sommeil est-il le chaînon manquant ?

ObjectiveTo examine the pathophysiologic mechanisms that may link circadian disorder and metabolic syndrome in bipolar disorder (BP).MethodA systematic review of the literature was conducted from January 2013 to January 2015, using the Medline and Cochrane databases, using the keywords “metabolic syndrome”, “obesity”, “leptin” and “circadian disorders”, “sleeping disorders” and cross-referencing them with “bipolar disorder”. The following types of publications were candidates for review: (i) clinical trials; (ii) studies involving patients diagnosed with bipolar disorder; (iii) studies involving patients with sleeping disorder; or (iv) data about metabolic syndrome.ResultsForty articles were selected. The prevalence of metabolic syndrome in BP was significantly higher compared to the general population (from 36 to 49% in the USA [Vancampfort, 2013]), and could be explained by several factors including reduced exercise and poor diet, genetic vulnerability, frequent depressive episodes, psychiatric comorbidity and psychotropic treatment. This high frequency of metabolic syndrome worsens the prognosis of these patients, increasing morbidity and mortality. Secondly, patients with BP experienced circadian and sleep disturbance, including modification in melatonin secretion. These perturbations are known to persist in periods of mood stabilization and are found in patients’ relatives. Circadian disturbances are factors of relapse in bipolar patients, and they may also have a role in the metabolic comorbidities of these patients. Recent studies show that in populations of patients with bipolar disorder, a correlation between circadian disturbance and metabolic parameters are found. To identify the pathophysiological pathway connecting both could lead to a better comprehension of the disease and new therapeutics. In the overall population, mechanisms have been identified linking circadian and metabolic disorder involving hormones like leptin and ghrelin. These hormones are keys to regulation of energy balance in the organism, via their action on the hypothalamus, and are also regulated by sleep. We have hypothesized that these pathways could be implicated in the vulnerability of bipolar patients to metabolic syndrome. This hypothesis is supported by several studies showing dysregulation in leptin and ghrelin secretion in multiple psychiatric disorders, including bipolar disorder, as well as genetic variations of leptin and ghrelin genes in these diseases. We also assume that other mechanisms may be at stake to explain this link, such as melatonin dysregulation and inflammation.ConclusionsCircadian and sleeping disorder may have a role in the prevalence of metabolic syndrome in BP. Hormones like leptin and ghrelin could be the link between these perturbations. Prevention and treatment of circadian disorder in BP may greatly reduce the occurrence of MetS in these patients. Being aware of this statement and taking care of these troubles should be a big step forward for treatment of BP.     

Anxiety symptoms and syndromes in bipolar children and adolescents

Anxiety disorders are relatively common in children and adolescents with bipolar disorder. Research to date indicates they may impact the onset, course, and treatment response of bipolar illness in children. Anxiety disorders often precede the onset of pediatric bipolar disorder. Family studies suggest first-degree relatives of bipolar patients are at increased risk for developing mood and anxiety disorders compared with relatives of individuals without mood disorders. Childhood adversity has been associated with higher rates of comorbid anxiety disorders and more severe illness course in bipolar patients. Preliminary study of the neurobiology of bipolar disorder with comorbid anxiety disorders suggests it may be neurophysiologically distinct from bipolar disorder without comorbid anxiety. Bipolar disorder with comorbid anxiety disorders has been associated with greater functional impairment and slower recovery. Prospective, longitudinal studies are needed to help us better understand the relationship between bipolar disorder and comorbid anxiety disorders so that opportunities for early intervention and effective treatment can be realized.     

Cyclothymia and typus melancholicus: empirical study on personality character of mood disorder]

PURPOSE: 1. To investigate whether depressive, cyclothymic, hyperthymic and irritable temperaments as identified by TEMPS-A are characteristic to monopolar or bipolar disorder. 2. To investigate the independency and to discuss the clinical validity of the temperaments. 3. To replicate the previous studies whether Typus Melancholicus is characteristic to monopolar disorder. 4. To investigate the relationship between Typus Melancholicus and mood dysregulation, and the relationship, if any, is characteristically observed with monopolar disorder. 5. To discuss the difference between monopolar and bipolar disorder in terms of personality character. SAMPLE: Monopolar and bipolar groups were recruited consecutively from the patients who received outpatient treatment at Kanto Medical Center between September and November, 2001. The age is between 18 and 60. The exclusion criteria were psychotic disorder, organic disorder, grave physical illness and non-remitted mood symptoms (HRSD > 11 and MRS > 13). Control group was selected from 1391 company employees who participated in TEMPS-A research project between May 2001 and May 2002, matching gender and age with monopolar and bipolar groups. The exclusion criterion was marked depressive symptom (CES-D > 16). STATISTICAL ANALYSIS: The statistical analyses were done with Kruskal-Wallis test and Mann-Whitney U test with Bonferroni's correction regarding the difference among the groups. Spearman coefficients were examined regarding the independency of temperaments. The relationship between Typus Melancholicus and mood dysregulation was examined by mono-regression analysis. RESULT AND DISCUSSION: Depressive and cyclothymic temperaments scores did not differ significantly between monopolar and bipolar. These scores were significantly higher in monopolar and bipolar than in control. Therefore, these temperaments are evidenced to be characteristic with mood disorder. But between monopolar and bipolar there was no significant difference. Irritable temperament score did not differ significantly among the three groups. This score showed a highly significant correlation with cyclothymic and depressive temperaments. Irritable temperament seems closely related with the personality character of mood disorder, however this temperament itself was not characteristic. Hyperthymic temperament score was mildly significantly lower in bipolar than in control. There was no other significant inter-group difference. This temperament hardly showed a correlation with other temperaments. Though hyperthymic temperament may be hypothesized characteristic with manic patients, the result did not support this hypothesis. Typus Melancholicus score did not differ significantly among three groups. This result contradicts with a number of previous studies. It seems that the prevalence of Typus Melancholicus among the groups should be further investigated. Typus Melancholicus showed a mild correlation with depressive temperament in monopolar and with depressive, cyclothymic and irritable and temperaments in bipolar. Regarding mono-regression analysis, no temperament predicted Typus Melancholicus formation in monopolar. Depressive, cyclothymic and irritable temperaments predicted significantly in bipolar. In control group, hyperthymic temperament predicted midly significantly, but the prediction rate was as small as 7%. These results seem to support the theories of Shimoda and Matussek that Typus Melancholicus characters are related with bipolar disorder. Between monopolar and bipolar, there was not much significant difference in terms of personality characteristics. This seems to suggest no marked personality character difference between these groups and supports Akiskal's concept of Bipolar Spectrum. CONCLUSION: 1. Depressive and Cyclothymic temperaments are characteristic with mood disorder. 2. Hyperthymic temperament is independent, but not characteristic with mood disorder. 3. Irritable temperament may be modifying the personality character of mood disorder. 4. Typus Melancholicus was not characteristic to monopolar disorder. 5. Significant relationship between Typus Melancholicus and mood dysregulation was observed in bipolar group. 6. There seems no substantial difference between monopolar and bipolar disorders in terms of personality character.     

Bipolar II disorder: arguments for and against a distinct diagnostic entity

Objective:  As a commitment to the International Society for Bipolar Disorders (ISBD) , a Task Force was developed to investigate the diagnostic value of bipolar II disorder.
Methods:  Task Force members worked jointly reviewing all relevant literature (original articles, reviews, letters, book chapters and congress presentations) that included 'bipolar II disorder' and/or 'hypomania' as key words.
Results:  Bipolar II disorder appears to be a reasonably valid and reliable diagnostic category yet often underdiagnosed or misdiagnosed as unipolar disorder or personality disorder. Moreover, it is officially recognized as a mental disorder in DSM-IV-TR but not in ICD-10, and many clinicians still regard it as a milder form of manic-depressive illness, despite data supporting high morbidity and mortality rates. In fact, bipolar II may be the most prevalent bipolar phenotype, although current diagnostic boundaries are seen as quite restrictive concerning the required duration for hypomania (4 days), the exclusion of hypomanic episodes potentially triggered by antidepressants and other substances, and the negligence of hypomanic mixed states. The course of bipolar II disorder is characterized by depressive predominant polarity, and its treatment is still controversial and poorly evidence-based.
Conclusions:  Bipolar II disorder is supported as a distinct category within mood disorders, but the definition and boundaries deserve a greater clarification in the DSM-V and ICD-11.     

Parental diagnoses in youth with narrow phenotype bipolar disorder or severe mood dysregulation

OBJECTIVE: Controversy exists regarding whether nonepisodic irritability and hyperarousal (severe mood dysregulation) is a phenotype of pediatric bipolar disorder. The authors compared axis I diagnoses in parents of children with narrow phenotype bipolar disorder and parents of youth with severe mood dysregulation. METHOD: Parents of youth with narrow phenotype bipolar disorder (proband N=33, parent N=42) and youth with severe mood dysregulation (proband N=30, parent N=37) were interviewed by clinicians who were blind to the child's diagnostic status using the Diagnostic Interview for Genetic Studies. RESULTS: Compared to parents of youth with severe mood dysregulation, parents of youth with narrow phenotype bipolar disorder were significantly more likely to be diagnosed with bipolar disorder. There were no other diagnostic differences between the two groups. CONCLUSIONS: These data suggest that narrow phenotype bipolar disorder may be distinct from severe mood dysregulation in terms of familial aggregation. Additionally, the familiality of narrow phenotype bipolar disorder and adult DSM-IV bipolar disorder is high.     

Are mood disorders and obesity related? A review for the mental health professional

OBJECTIVE: We reviewed evidence regarding a possible relationship between mood disorders and obesity to better inform mental health professionals about their overlap. METHOD: We performed a MEDLINE search of the English-language literature for the years 1966-2003 using the following terms: obesity, overweight, abdominal, central, metabolic syndrome, depression, mania, bipolar disorder, binge eating, morbidity, mortality, cardiovascular, diabetes, cortisol, hypertriglyceridemia, sympathetic, family history, stimulant, sibutramine, antiobesity, antidepressant, topiramate, and zonisamide. We evaluated studies of obesity (and related conditions) in persons with mood disorders and of mood disorders in persons with obesity. We also compared studies of obesity and mood disorders regarding phenomenology, comorbidity, family history, biology, and pharmacologic treatment response. RESULTS: The most rigorous clinical studies suggest that (1). children and adolescents with major depressive disorder may be at increased risk for developing overweight; (2). patients with bipolar disorder may have elevated rates of overweight, obesity, and abdominal obesity; and (3). obese persons seeking weight-loss treatment may have elevated rates of depressive and bipolar disorders. The most rigorous community studies suggest that (1). depression with atypical symptoms in females is significantly more likely to be associated with overweight than depression with typical symptoms; (2). obesity is associated with major depressive disorder in females; and (3). abdominal obesity may be associated with depressive symptoms in females and males; but (4). most overweight and obese persons in the community do not have mood disorders. Studies of phenomenology, comorbidity, family history, biology, and pharmacologic treatment response of mood disorders and obesity show that both conditions share many similarities along all of these indices. CONCLUSION: Although the overlap between mood disorders and obesity may be coincidental, it suggests the two conditions may be related. Clinical and theoretical implications of this overlap are discussed, and further research is called for.     

Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults

Nusslock R, Almeida JRC, Forbes EE, Versace A, Frank E, LaBarbara EJ, Klein CR, Phillips ML. Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. Bipolar Disord 2012: 14: 249–260. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Bipolar disorder may be characterized by a hypersensitivity to reward‐relevant stimuli, potentially underlying the emotional lability and dysregulation that characterizes the illness. In parallel, research highlights the predominant role of striatal and orbitofrontal cortical (OFC) regions in reward‐processing and approach‐related affect. We aimed to examine whether bipolar disorder, relative to healthy, participants displayed elevated activity in these regions during reward processing. Methods: Twenty‐one euthymic bipolar I disorder and 20 healthy control participants with no lifetime history of psychiatric disorder underwent functional magnetic resonance imaging (fMRI) scanning during a card‐guessing paradigm designed to examine reward‐related brain function to anticipation and receipt of monetary reward and loss. Data were collected using a 3T Siemens Trio scanner. Results: Region‐of‐interest analyses revealed that bipolar disorder participants displayed greater ventral striatal and right‐sided orbitofrontal [Brodmann area (BA) 11] activity during anticipation, but not outcome, of monetary reward relative to healthy controls (p < 0.05, corrected). Whole‐brain analyses indicated that bipolar disorder, relative to healthy, participants also displayed elevated left‐lateral OFC (BA 47) activity during reward anticipation (p < 0.05, corrected). Conclusions: Elevated ventral striatal and OFC activity during reward anticipation may represent a neural mechanism for predisposition to expansive mood and hypo/mania in response to reward‐relevant cues that characterizes bipolar disorder. Our findings contrast with research reporting blunted activity in the ventral striatum during reward processing in unipolar depressed individuals, relative to healthy controls. Examination of reward‐related neural activity in bipolar disorder is a promising research focus to facilitate identification of biological markers of the illness.     

Emotion processing and regulation in bipolar disorder: a review

Townsend J, Altshuler LL. Emotion processing and regulation in bipolar disorder: a review.
Bipolar Disord 2012: 14: 326–339. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Bipolar disorder (BP) is characterized by a dysfunction of mood, alternating between states of mania/hypomania and depression. Thus, the primary abnormality appears to be an inability to regulate emotion, the result of which is emotional extremes. The purpose of this paper is to review the current functional magnetic resonance imaging (fMRI) literature on adult patients with BP using emotion processing or regulation paradigms. Methods: A search was conducted on PubMed using the keywords: bipolar disorder, fMRI, mania, bipolar depression, bipolar euthymia, emotion, and amygdala. Only those studies that were conducted in adult patients using an emotion activation task were included in the final review. Results: Using tasks that assess neural functioning during emotion processing and emotion regulation, many fMRI studies have examined BP subjects during mania and euthymia. Fewer fMRI studies have been conducted during depression, and fewer still have included the same subjects in multiple mood states. Despite these limitations, these studies have demonstrated specific abnormalities in frontal–limbic regions. Using a variety of paradigms, investigators have specifically evaluated the amygdala (a structure within the limbic system known to be critical for emotion) and the prefrontal cortex (PFC) (a region known to have a regulatory function over the limbic system). Conclusions: These investigations reveal that amygdala activation varies as a function of mood state, while the PFC remains persistently hypoactivated across mood states. Emotional dysregulation and lability in mania and depression may reflect disruption of a frontal–limbic functional neuroanatomical network.     

Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children?

Margulies DM, Weintraub S, Basile J, Grover PJ, Carlson GA. Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children? Bipolar Disord 2012: 14: 488–496. © 2012 The Authors Journal compilation © 2012 John Wiley & Sons A/S. Objectives: The frequency of diagnosis of bipolar disorder has risen dramatically in children and adolescents. The DSM‐V Work Group has suggested a new diagnosis termed disruptive mood dysregulation disorder (DMDD) (formerly temper dysregulation disorder with dysphoria) to reduce the rate of false diagnosis of bipolar disorder in young people. We sought to determine if the application of the proposed diagnostic criteria for DMDD would reduce the rate of diagnosis of bipolar disorder in children. Patients and methods: Eighty‐two consecutively hospitalized children, ages 5 to 12 years, on a children’s inpatient unit were rigorously diagnosed using admission interviews of the parents and the child, rating scales, and observation over the course of hospitalization. Results: Overall, 30.5% of inpatient children met criteria for DMDD by parent report, and 15.9% by inpatient unit observation. Fifty‐six percent of inpatient children had parent‐reported manic symptoms. Of those, 45.7% met criteria for DMDD by parent‐report, though only 17.4% did when observed on the inpatient unit. Conclusion: Although DMDD does decrease the rate of diagnosis of bipolar disorder in children, how much depends on whether history or observation is used.     

Bipolar depression: phenomenological overview and clinical characteristics

OBJECTIVES: There has been increasing interest in the depressed phase of bipolar disorder (bipolar depression). This paper aims to review the clinical characteristics of bipolar depression, focusing upon its prevalence and phenomenology, related neuropsychological dysfunction, suicidal behaviour, disability and treatment responsiveness. METHODS: Studies on the prevalence of depression in bipolar disorder, the comparative phenomenology of bipolar and unipolar depression, as well as neuropsychology and brain imaging studies, are reviewed. To identify relevant papers, a literature search using MEDLINE and PubMed was undertaken. RESULTS: Depression is the predominant mood disturbance in bipolar disorder, and most frequently presents as subsyndromal, minor or dysthymic depression. Compared with major depressive disorder (unipolar depression), bipolar depression is more likely to manifest with psychosis, melancholic symptoms, psychomotor retardation (in bipolar I disorder) and 'atypical' symptoms. The few neuropsychological studies undertaken indicate greater impairment in bipolar depression. Suicide rates are high in bipolar disorder, with suicidal ideation, suicide attempts and completed suicides all occurring predominantly in the depressed phase of this condition. Furthermore, the depressed phase (even subsyndromal) appears to be the major contributant to the disability related to this condition. CONCLUSIONS: The significance of the depressed phase of bipolar disorder has been markedly underestimated. Bipolar depression accounts for most of the morbidity and mortality due to this illness. Current treatments have significant limitations.     

Different psychophysiological and behavioral responses elicited by frustration in pediatric bipolar disorder and severe mood dysregulation

OBJECTIVE: Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrow-phenotype bipolar disorder (i.e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i.e., healthy comparison children). METHOD: Subjects with severe mood dysregulation (N=21) or narrow-phenotype bipolar disorder (N=35) and comparison subjects (N=26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured. RESULTS: The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrow-phenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity. CONCLUSIONS: Results indicate that while irritability is an important feature of severe mood dysregulation and narrow-phenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity.     

Suicidality in pediatric bipolar disorder: predictor or outcome of family processes and mixed mood presentation?

Algorta GP, Youngstrom EA, Frazier TW, Freeman AJ, Youngstrom JK, Findling RL. Suicidality in pediatric bipolar disorder: predictor or outcome of family processes and mixed mood presentation?
Bipolar Disord 2011: 13: 76–86. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objective: Pediatric bipolar disorder (PBD) involves a potent combination of mood dysregulation and interpersonal processes, placing these youth at significantly greater risk of suicide. We examined the relationship between suicidal behavior, mood symptom presentation, family functioning, and quality of life (QoL) in youth with PBD. Methods: Participants were 138 youths aged 5–18 years presenting to outpatient clinics with DSM‐IV diagnoses of bipolar I disorder (n = 27), bipolar II disorder (n = 18), cyclothymic disorder (n = 48), and bipolar disorder not otherwise specified (n = 45). Results: Twenty PBD patients had lifetime suicide attempts, 63 had past or current suicide ideation, and 55 were free of suicide ideation and attempts. Attempters were older than nonattempters. Suicide ideation and attempts were linked to higher depressive symptoms, and rates were even higher in youths meeting criteria for the mixed specifier proposed for DSM‐5. Both suicide ideation and attempts were associated with lower youth QoL and poorer family functioning. Parent effects (with suicidality treated as outcome) and child effects (where suicide was the predictor of poor family functioning) showed equally strong evidence in regression models, even after adjusting for demographics. Conclusions: These findings underscore the strong association between mixed features and suicidality in PBD, as well as the association between QoL, family functioning, and suicidality. It is possible that youths are not just a passive recipient of family processes, and their illness may play an active role in disrupting family functioning. Replication with longitudinal data and qualitative methods should investigate both child and parent effect models.     

Bipolar disorder in women: reproductive events and treatment considerations

OBJECTIVE: Bipolar disorders are prevalent in women. Women with bipolar disorder often present with different clinical features than men. Reproductive events and hormonal treatments may impact the course of bipolar disorder. Our main objectives are to i) assess the impact of reproductive events on the course of the disorder, and ii) to discuss the relationships between reproductive events and psychiatric treatments. METHOD: A literature search was conducted of MEDLINE journals from 1965 to present. Manual literature searches were also conducted. We review the presentation, clinical course, and treatment considerations of bipolar disorder in women, with emphasis on treatment considerations in the context of reproductive events. Treatment-related issues such as teratogenicity, breastfeeding, polycystic ovarian syndrome, weight gain and obesity, and medication interactions with oral contraceptives are reviewed. RESULTS: Women with bipolar disorder may be more vulnerable to mood episodes in the context of reproductive events, particularly postpartum. In women of reproductive age, mood stabilizers must be selected with teratogenic risks in mind, with the highest reported risks in pregnancy with valproate, and the greatest concern during breastfeeding with lithium use. In the areas of the perimenopause and polycycstic ovarian syndrome, more data are needed to advise treatment decisions. CONCLUSION: We urgently need further study in these areas to deliver care that is appropriate to women with bipolar disorder.     

The longitudinal course of bipolar disorder as revealed through weekly text messaging: a feasibility study

Bopp JM, Miklowitz DJ, Goodwin GM, Stevens W, Rendell JM, Geddes JR. The longitudinal course of bipolar disorder as revealed through weekly text messaging: a feasibility study.
Bipolar Disord 2010: 12: 327–334. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: To examine the feasibility of collecting course of illness data from patients with bipolar I and II disorder, using weekly text‐messaged mood ratings, and to examine the time trajectory of symptom ratings based on this method of self‐report. Methods: A total of 62 patients with bipolar I (n = 47) or II (n = 15) disorder provided mood data in response to weekly cell phone text messages (n = 54) or e‐mail prompts (n = 8). Participants provided weekly ratings using the Altman Self‐Rating Mania Scale and the Quick Inventory of Depressive Symptoms–Self Report. Patients with bipolar I and II disorder, and men and women, were compared on percentages of time in depressive or manic mood states over up to two years. Results: Participants provided weekly ratings over an average of 36 (range 1–92) weeks. Compliance with the procedure was 75%. Overall, participants reported depressive symptoms 47.7% of the time compared to 7% of entries reflecting manic symptoms, 8.8% reflecting both depressive and manic symptoms, and 36.5% reflecting euthymic mood. Participants with bipolar I disorder reported more days of depression and were less likely to improve with time than participants with bipolar II disorder. Gender differences observed at the beginning of the study were not observed at follow‐up. Conclusions: The results are similar to those of other longitudinal studies of bipolar disorder that use traditional retrospective, clinician‐gathered mood data. Text‐message‐based symptom monitoring during routine follow‐up may be a reliable alternative to in‐person interviews.     

Severe mood dysregulation, irritability, and the diagnostic boundaries of bipolar disorder in youths

In recent years, increasing numbers of children have been diagnosed with bipolar disorder. In some cases, children with unstable mood clearly meet current diagnostic criteria for bipolar disorder, and in others, the diagnosis is unclear. Severe mood dysregulation is a syndrome defined to capture the symptomatology of children whose diagnostic status with respect to bipolar disorder is uncertain, that is, those who have severe, nonepisodic irritability and the hyperarousal symptoms characteristic of mania but who lack the well-demarcated periods of elevated or irritable mood characteristic of bipolar disorder. Levels of impairment are comparable between youths with bipolar disorder and those with severe mood dysregulation. An emerging literature compares children with severe mood dysregulation and those with bipolar disorder in longitudinal course, family history, and pathophysiology. Longitudinal data in both clinical and community samples indicate that nonepisodic irritability in youths is common and is associated with an elevated risk for anxiety and unipolar depressive disorders, but not bipolar disorder, in adulthood. Data also suggest that youths with severe mood dysregulation have lower familial rates of bipolar disorder than do those with bipolar disorder. While youths in both patient groups have deficits in face emotion labeling and experience more frustration than do normally developing children, the brain mechanisms mediating these pathophysiologic abnormalities appear to differ between the two patient groups. No specific treatment for severe mood dysregulation currently exists, but verification of its identity as a syndrome distinct from bipolar disorder by further research should include treatment trials.     

Unmet needs in bipolar depression

Bipolar disorders, particularly bipolar spectrum disorders, frequently go unrecognized and undiagnosed by clinicians and thus remain untreated or inappropriately treated. Although the symptoms of bipolar I disorder are widely acknowledged and recognized among clinicians, epidemiology sampling studies over the past several years have found that bipolar II disorder and bipolar spectrum disorders are likely to be more prevalent and more challenging to diagnose, particularly as depressive presentations are far more common in these groups. Bipolar disorder is associated with increased morbidity and mortality, as well as higher healthcare costs, but it is unclear how much of the consequences of bipolar disorder are unrecognized in the face of poor recognition of bipolar II and bipolar spectrum disorders. This article addresses challenges in diagnosing and treating bipolar disorder in the face of a depressive episode, and offers guidelines for recognizing and appropriately managing these patients. Studies with the newer anticonvulsant mood stabilizer lamotrigine have shown antidepressant effects in bipolar disorder, and may fill an unmet need for treatment options in patients who present with depression in the context of bipolar disorder.     

Revisiting depressive-prone bipolar disorder: polarity of initial mood episode and disease course among bipolar I systematic treatment enhancement program for bipolar disorder participants.

BACKGROUND: We examined the hypothesis that a first depressive rather than manic episode in bipolar disorder might herald a subsequent course notable for greater burden of depressive symptoms. METHODS: We analyzed retrospective data on the polarity of first mood episode obtained from 704 bipolar I subjects entering the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. Subjects with an initial manic or depressive episode and those in whom both poles occurred within the same year were compared. RESULTS: Depressive-onset bipolar disorder was more common in women and those with earlier onset of illness. Adjusting for these differences, it was significantly associated with more lifetime depressive episodes and a greater proportion of time with depression and anxiety in the year prior to study entry. CONCLUSIONS: Polarity of first mood episode may be useful in distinguishing subsets of bipolar patients at risk for a more chronic course.     

Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study

OBJECTIVES: To determine if bipolar disorder is accurately diagnosed in clinical practice and to assess the effects of antidepressants on the course of bipolar illness. METHOD: Charts of outpatients with affective disorder diagnoses seen in an outpatient clinic during 1 year (N = 85 with bipolar or unipolar disorders) were reviewed. Past diagnostic and treatment information was obtained by patient report and systematic psychiatric history. Bipolar diagnosis was based on DSM-IV criteria using a SCID-based interview. RESULTS: Bipolar disorder was found to be misdiagnosed as unipolar depression in 37% of patients who first see a mental health professional after their first manic/hypomanic episode. Antidepressants were used earlier and more frequently than mood stabilizers, and 23% of this unselected sample experienced a new or worsening rapid-cycling course attributable to antidepressant use. CONCLUSION: These results suggest that bipolar disorder tends be misdiagnosed as unipolar major depressive disorder and that antidepressants seem to be associated with a worsened course of bipolar illness. However, this naturalistic trial was uncontrolled, and more controlled research is required to confirm or refute these findings.