A two-illness model of bipolar disorder

The current approach to mood disorders is that bipolar disorder, comprising both mania and depression, is a discreet illness distinct from unipolar depression. This formulation has profoundly influenced the approach to understanding the biology and etiology of these disorders, as well as the manner in which the various phases of bipolar disorder are treated. Our new model suggests that bipolar disorder comprises two distinct illnesses, mania and depression, and that bipolar depression is no different from unipolar depression. Studies of clinical syndromes, course of illness, family history and genetics, biological factors, and treatment response data directly or indirectly support this new model.     

Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study

Chaves OC, Lombardo LE, Bearden CE, Woolsey MD, Martinez DM, Barrett JA, Miller AL, Velligan DI, Glahn DC. Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study.
Bipolar Disord 2011: 13: 118–123. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objective: Despite evidence that individuals with bipolar disorder have neurocognitive impairment that persists during euthymia, the impact of changes in affective symptoms on cognitive function has not been well established. Here, we sought to determine whether specific neurocognitive functions are sensitive to mood changes in individuals with bipolar disorder assessed three months apart without changes in treatment regimen. Methods: A total of 29 individuals with DSM‐IV bipolar disorder and 30 healthy controls participated in the study. All participants received a comprehensive neuropsychological assessment and ratings of depressive [Hamilton Depression Rating Scale (HAMD)] and manic [Young Mania Rating Scale (YMRS)] symptoms at baseline and follow‐up. Changes in symptoms over time were calculated and were examined in relation to changes in neurocognitive performance. Results: At baseline, clinically stable but symptomatic patients were impaired on measures of speed of processing and attention. Over the three‐month follow‐up period, HAMD scores changed by 6 points on average [range: ?10 to +18] and YMRS scores changed by 5.31 points on average [range ?11 to +15]. Changes in depressive symptoms were correlated with poorer verbal fluency, while no relationship between manic symptoms and neuropsychological performance was detected. Conclusions: Individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood.     

Impact of psychosis in bipolar disorder during manic episodes*

Abstract

Objectives: To evaluate the effect of psychosis on prognosis as measured by the course of a manic episode, symptoms severity and time to remission and identify existing differences in positive and negative symptoms between psychotic and non-psychotic patients.

Study design: 40 bipolar patients presenting with a diagnosis of acute mania were enrolled (18 psychotic patients and 22 non-psychotic patients) in this cross-sectional study. Subjects were required to complete two self-reported questionnaires, the Young Mania Rating Scale (YMRS) for manic symptoms, and Positive and Negative Symptoms Scale (PANSS) for psychotic symptoms. Rating scales were administered at baseline and then again after three weeks of pharmacologic treatment.

Results: There were no differences in socio-demographic characteristics between psychotic and non-psychotic subjects. Psychosis was associated with higher scores on the YMRS and PANSS (increased symptoms severity), compared to non-psychotic patients. Both groups demonstrated clinical improvement and remission, with scores amongst psychotic patients remaining higher. Groups were similar in symptomatology except with regards to psychotic symptoms (the content, insight, delusions, hallucinations, grandiosity, poor rapport and unusual thoughts).

Conclusions: Psychosis can be considered a severity index in bipolar disorder, with decreased severity and overall clinical improvement and remission taking place in response to pharmacotherapy.     

Clinical course of children with a depressive spectrum disorder and transient manic symptoms

Nadkarni RB, Fristad MA. Clinical course of children with a depressive spectrum disorder and transient manic symptoms.
Bipolar Disord 2010: 12: 494–503. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: To assess rates of conversion to bipolar spectrum disorder (BPSD) and risk factors associated with conversion in children with depressive spectrum disorders (DSD) and transient manic symptoms (TMS) over 18 months. TMS are manic‐like symptoms of insufficient duration or number to warrant a diagnosis of BPSD. Methods: Participants were 165 children (mean = 9.9 years, SD = 1.3) with mood disorders from the Multi‐Family Psychoeducational Psychotherapy (MF‐PEP) treatment study: 37 with DSD+TMS, 13 with DSD, and 115 with BPSD. All were assessed with standardized instruments on four occasions over 18 months, with half receiving MF‐PEP after their baseline assessment and half receiving MF‐PEP after a one‐year wait‐list condition. Results: At baseline, the Children’s Global Assessment Scale scores did not differ significantly between the DSD+TMS, DSD, and BPSD groups. Conversion rates to BPSD were significantly higher for the DSD+TMS group (48.0%) compared to the DSD group (12.5%). Conversion was significantly more frequent for participants in the one‐year wait‐list control group (60%) compared to the immediate treatment group (16%). Clinical presentation, family environment, and family history did not differ significantly between the small subset of DSD+TMS participants who did convert to BPSD at follow‐up and those who did not convert. Baseline functional impairment was greater for the converted group than the non‐converted group. Conclusions: Transient manic symptoms are a risk factor for eventual conversion to BPSD; psychoeducational psychotherapy may be protective. As this exploratory study had a small sample size and did not correct for multiple comparisons, additional studies with larger sample sizes are needed.     

Factors related to hospitalization in elderly manic patients with early and late-onset bipolar disorder

OBJECTIVE: To identify factors contributing to relapse and hospitalization in elderly patients with bipolar disorder. METHOD: Retrospective chart review surveyed consecutive patients over age 65 admitted to the Johns Hopkins Hospital for a manic episode over a five year period (n=73). Factors precipitating index admission were compared in patients with early-onset bipolar disorder (age 45, n=35). RESULTS: The distribution of ages of onset of bipolar disorder was most consistent with a bimodal pattern with a cut-point at age 45. Early-onset patients were more likely to have been aggressive and threatening prior to admission (p=0.014) compared to late-onset patients and were more likely to have been brought to the emergency room on emergency petition for evaluation (p=0.028). Early-onset patients were also more likely to have been non-adherent with prescribed psychiatric medication (p=0.032). CONCLUSIONS: Relapse and rehospitalization were common among elderly manic patients with early-onset and late-onset bipolar disorder. Strategies which improve medication adherence are needed to help prevent recurring hospitalization.     

COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder

Soeiro‐de‐Souza MG, Machado‐Vieira R, Soares Bio D, Do Prado CM, Moreno RA. COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. Bipolar Disord 2012: 14: 554–564. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S. Objective: The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol‐O‐methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. Methods: Seventy‐two symptomatic, medication‐free subjects with bipolar I disorder (BD‐I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. Results: Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. Conclusions: Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state‐dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings.     

Differential effects of depression and mania symptoms on social adjustment: prospective study in bipolar disorder

Morriss R, Yang M, Chopra A, Bentall R, Paykel E, Scott J. Differential effects of depression and mania symptoms on social adjustment: prospective study in bipolar disorder.
Bipolar Disord 2013: 15: 80–91. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd. Objectives: Previous studies of social adjustment in bipolar disorder have been cross‐sectional and small in sample size, have examined a limited number of roles, or were not controlled for baseline mood and other clinical, social, or treatment confounders. We aimed to prospectively explore the strength and stability of correlations between depression and mania‐type symptoms and impairment in a broad range of social adjustment roles and domains. Methods: Multilevel modeling analysis of correlation coefficients between depression and mania‐type symptoms with roles and domains of the modified social adjustment scale (overall, work, social/leisure, extended family, marital, parental social adjustment roles, performance, interpersonal behavior, friction, dependency, overactivity domains) was used. Interview assessments were made at eight‐week intervals beginning at eight weeks and continuing through 72 weeks after baseline in 253 patients in a multicenter randomized controlled trial. Results: After controlling for baseline mood episodes, and other clinical, social, and treatment variables, depression symptoms showed strong and stable correlations over time with performance, overall social adjustment, and the work role; and a moderate but stable relationship with interpersonal behavior. The relationships of depression symptoms with the other roles were weak, non‐significant, or not stable. For mania‐type symptoms, only the correlation with interpersonal friction was moderately strong and reasonably stable over time. Mood episodes, substance use disorder, and borderline/antisocial personality disorder increased role impairment, while employment and marriage mildly decreased it. Conclusions: Depression and mania‐type symptoms have specific effects on social adjustment in bipolar I disorder. Depression symptoms are correlated strongly with performance and moderately with interpersonal behavior, while mania‐type symptoms are correlated moderately with interpersonal friction.     

Changes in insight among patients with bipolar I disorder: a 2-year prospective study

OBJECTIVES: The aim of this 2-year prospective study was to examine changes in insight among bipolar patients with different clinical courses. METHODS: A cohort of 65 patients with bipolar I disorder in remission was recruited for this study. They received six follow-up assessments over a 2-year period. The Schedule of Assessment of Insight-Expanded version (SAI-E) was used to determine their levels of insight, while the Young Mania Rating Scale (YMRS) and the Hamilton Rating Scale for Depression (HAM-D) were used to determine affective symptoms. Types of changes in insight among bipolar patients were analyzed according to the different clinical courses during the 2-year follow-up period. RESULTS: Insight in consistently stable patients was steady during the 2-year period. Insight decreased during the manic period in patients with only a single manic episode as well as in those with repeated manic episodes. However, insight returned to the pre-episode level for patients with only a single manic episode, but did not for most of the patients with repeated episodes. No changes in insight were observed during depressive episodes for either patients with a single or those with repeated depressive episodes. CONCLUSIONS: The types of insight changes among bipolar patients during the 2-year period were various and depended on the different clinical courses. Frequent mood disturbance episodes may cause patient insight to deteriorate.     

Concurrent tracking of alcohol use and bipolar disorder symptoms

OBJECTIVES: Alcohol use disorders (AUDs) are common co-occurring conditions in patients with bipolar disorder (BD), but it is unclear whether or not AUD and BD symptoms are temporally correlated. The primary aim of this analysis was to examine concurrent symptom tracking and how the relative onsets of AUD and BD influence the concurrent tracking of symptoms. METHODS: Participants met DSM-IV criteria for bipolar I disorder, manic or mixed, with no prior hospitalizations and minimal treatment. Patients were rated for alcohol use and bipolar symptom severity on a weekly basis for up to 7 years. For analysis purposes, patients were placed into groups with no AUD (BD Only; n = 21), onset of AUD either concurrent with or after the onset of bipolar symptoms (BD First; n = 32), and onset of AUD at least 1 year before the onset of bipolar symptoms (AUD First; n = 18). RESULTS: None of the patient groups demonstrate consistent positive or negative temporal correlations between alcohol use and affective symptoms. However, there were significant between-group differences on the relationship of symptom tracking and age of BD onset. For the AUD First group, the correlation between age of BD onset and symptom tracking was positive 0.41. However, for the BD First and BD Only groups the correlations were negative (-0.32 and -0.41, respectively). Moreover, for patients whose BD onset was < or =18 years old, the correlation between age of onset and tracking was -0.47. CONCLUSIONS: These findings suggest that although there is no direct temporal correlation of AUD and BD symptoms in subgroups of BD patients, age at illness onset contributes to the complex relationship between BD and AUD. For younger patients there may be a greater likelihood that alcohol use and bipolar symptoms increase or decrease in unison.     

Aggression and substance abuse in bipolar disorder

Objectives:  The goal of this retrospective study was to examine factors differentiating persons with bipolar disorder who did or did not have comorbid lifetime substance use disorders (SUD) at an index assessment. We also explored the chronology of onset of mood and SUD.
Methods:  We studied 146 subjects with DSM-defined bipolar disorder. Subgroups with and without lifetime SUD were compared on demographic and clinical measures.
Results:  Substance abuse disorders in this bipolar sample were associated with male sex, impulsive-aggressive traits, comorbid conduct and Cluster B personality disorders, number of suicide attempts and earlier age at onset of a first mood episode. In a multivariable logistic regression analysis, male sex and aggression and possibly earlier age at mood disorder onset were associated with SUD. In those with or without SUD, the first mood episode tended to be depressive and to precede the onset of SUD.
Conclusions:  In persons with bipolar disorder, an earlier age of onset and aggressive traits appear to be factors associated with later development of comorbid SUD.     

The role of dopamine in bipolar disorder

Objective: Despite effective pharmacological treatments for bipolar disorder, we still lack a comprehensive pathophysiological model of the illness. Recent neurobiological research has implicated a number of key brain regions and neuronal components in the behavioural and cognitive manifestations of bipolar disorder. Dopamine has previously been investigated in some depth in bipolar disorder, but of late has not been a primary focus of attention. This article examines the role of dopamine in bipolar disorder, incorporating recent advances into established models where possible. Methods: A critical evaluation of the literature was undertaken, including a review of behavioural, neurochemical, receptor, and imaging studies, as well as genetic studies focusing on dopamine receptors and related metabolic pathways. In addition, pharmacologic manipulation of the central dopaminergic pathways and comparisons with other disease states such as schizophrenia were considered, principally as a means of exploring the hypothesised models. Results: Multiple lines of evidence, including data from pharmacological interventions and structural and functional magnetic resonance imaging studies, suggest that the dopaminergic system may play a central role in bipolar disorder. Conclusion: Future research into the pathophysiological mechanisms of bipolar disorder and the development of new treatments for bipolar disorder should focus on the dopaminergic system.     

Polarity at illness onset in bipolar I disorder and clinical course of illness

Objectives:  Studies have suggested that episode polarity at illness onset in bipolar disorder may be predictive of some aspects of lifetime clinical characteristics. We here examine this possibility in a large, well-characterized sample of patients with bipolar I disorder.
Methods:  We assessed polarity at onset in patients with bipolar I disorder (N = 553) recruited as part of our ongoing studies of affective disorders. Lifetime clinical characteristics of illness were compared in patients who had a depressive episode at first illness onset (n = 343) and patients who had a manic episode at first illness onset (n = 210).
Results:  Several lifetime clinical features differed between patients according to the polarity of their onset episode of illness. A logistic regression analysis showed that the lifetime clinical features significantly associated with a depressive episode at illness onset in our sample were: an earlier age at illness onset; a predominantly depressive polarity during the lifetime; more frequent and more severe depressive episodes; and less prominent lifetime psychotic features.
Conclusions:  Knowledge of pole of onset may help the clinician in providing prognostic information and management advice to an individual with bipolar disorder.     

Juvenile bipolar disorder

OBJECTIVE: Bipolar disorder in children and adolescents is less well studied than bipolar disorder in adults. This review addresses issues related to its underdiagnosis, precursors of bipolarity, comorbidity, natural course and treatment. METHOD: Literature from Medline and other searches, and earlier relevant articles including references from recent review articles on juvenile bipolarity were reviewed. RESULTS: Bipolar disorder in juveniles is underdiagnosed and misdiagnosed on various counts. Few recent studies have reported high rates of comorbid attention deficit and disruptive disorders, prompting some researchers to consider them as probable developmental precursors of juvenile bipolarity. There is also evidence to suggest that some juvenile depression could be pre-bipolar, and that certain temperamental predispositions are probable precursors to bipolarity. Limited data on the natural course and outcome suggest that juvenile bipolar disorder is a highly recurring illness as in adults, and that it is associated with significant functional impairment. The psychopharmacological treatment of juvenile bipolar disorder is remarkably understudied, and treatment is often based on studies of adults. CONCLUSION: There is a need for epidemiological studies of juvenile bipolar disorder. Similarly, there is an urgent need for the methodologically rigorous studies to establish the efficacy of various antimanic drugs. Finally, issues related to comorbidity and temperamental predispositions to juvenile bipolarity need greater clarity, as they may have important treatment and research implications.     

Evidence-based options for treatment-resistant adult bipolar disorder patients

Poon SH, Sim K, Sum MY, Kuswanto CN, Baldessarini RJ. Evidence‐based options for treatment‐resistant adult bipolar disorder patients. Bipolar Disord 2012: 14: 573–584. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments. Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients. Methods: We performed a literature review of the research findings related to treatment‐resistant BD reported through February 2012. Results: Therapeutic trials for treatment‐resistant bipolar mania are uncommon, and provide few promising leads other than the use of clozapine. Far more pressing challenges are the depressive‐dysthymic‐dysphoric‐mixed phases of BD and long‐term prophylaxis. Therapeutic trials for treatment‐resistant bipolar depression have assessed anticonvulsants, modern antipsychotics, glutamate [N‐methyl‐D‐aspartate (NMDA)] antagonists, dopamine agonists, calcium‐channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation—all of which are promising but limited in effectiveness. Several innovative pharmacological treatments (an anticholinesterase, a glutamine antagonist, a calcium‐channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive‐behavior therapy have some support for long‐term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited. Conclusions: Most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow‐up, and lacked replication. Clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow‐up.     

Social competence and observer-rated social functioning in bipolar disorder

Depp CA, Mausbach BT, Harvey PD, Bowie CR, Wolyniec PS, Thornquist MH, Luke JR, McGrath JA, Pulver AE, Patterson TL. Social competence and observer‐rated social functioning in bipolar disorder.
Bipolar Disord 2010: 12: 843–850. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: Impairment in social functioning appears to be common in bipolar disorder, although estimates have been derived largely from self‐report measures. We examined performance‐based and observer‐based ratings of social competence and functioning and assessed the contribution of symptoms and neurocognitive ability to social functioning in bipolar disorder. Methods: In this cross‐sectional study, 164 subjects with bipolar disorder were administered the performance‐based Social Skills Performance Assessment (SSPA), rated by an informant on the Specific Level of Functioning (SLOF)–Interpersonal subscale, received clinical ratings of depression and manic symptoms, and performed neurocognitive tests. We assessed the proportion of patients exhibiting social deficits and examined the associations between composite measures of neurocognitive ability, depression and manic symptoms, and SSPA scores with informant‐rated, real‐world social functioning. Results: Mean age of the sample was 47.6 years (SD = 14.1). Subjects were experiencing, on average, mild levels of depression and minimal manic symptoms. A total of 29% exhibited norm‐referenced impairment on the SSPA, and 64% registered at least one impairment on SLOF items; unemployed subjects had lower SSPA and SLOF ratings. Neurocognitive performance correlated with both performance‐based and observer‐rated social functioning, whereas depressive and manic symptoms correlated only with observer‐rated social impairments. In multivariate models, depression was the most potent association with social functioning, and impairment in social competence (i.e., capacity) increased the strength of the relationships between depression and neurocognitive impairment and social functioning (i.e., real‐world functioning). Conclusions: Our study confirmed the negative relationship of bipolar depression with social functioning. A subgroup of outpatients with bipolar disorder has impaired social competence, which, when present, worsened the impact of depression and cognitive impairment on social functioning.