Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features

Bipolar mixed states combine depressive and manic features, presenting diagnostic and treatment challenges and reflecting a severe form of the illness. DSM-IV criteria for a mixed state require combined depressive and manic syndromes, but a range of mixed states has been described clinically. A unified definition of mixed states would be valuable in understanding their diagnosis, mechanism and treatment implications. We investigated the manner in which depressive and manic features combine to produce a continuum of mixed states. In 88 subjects with bipolar disorder (DSM-IV), we evaluated symptoms and clinical characteristics, and compared depression-based, mania-based, and other published definitions of mixed states. We developed an index of the extent to which symptoms were mixed (Mixed State Index, MSI) and characterized its relationship to clinical state. Predominately manic and depressive mixed states using criteria from recent literature, as well as Kraepelinian mixed states, had similar symptoms and MSI scores. Anxiety correlated significantly with depression scores in manic subjects and with mania scores in depressed subjects. Discriminant function analysis associated mixed states with symptoms of hyperactivity and negative cognitions, but not subjective depressive or elevated mood. High MSI scores were associated with severe course of illness. For depressive or manic episodes, characteristics of mixed states emerged with two symptoms of the opposite polarity. This was a cross-sectional study. Mixed states appear to be a continuum. An index of the degree to which depressive and manic symptoms combine appears useful in identifying and characterizing mixed states. We propose a depressive or manic episode with three or more symptoms of the opposite polarity as a parsimonious definition of a mixed state.     

Treatment of acute mania

The DSM-IV criteria for mania require: a distinct period that represents a break from pre-morbid functioning, a duration of at least one week, elevated or irritable mood, at least three to four classical manic signs and symptoms and the absence of any physical factors. Although not specifically mentioned in the ICD-10 or the DSM-IV definitions, delusional, hallucinatory, even first-rank, psychotic experiences can occur in mania. Acute mania can be subdivided into classical pure mania, mania with mood-congruent or mood-incongruent psychosis, mixed state and rapid-cycling mania. One quarter to two thirds of all manic episodes are associated with delusions, while 13% to 40% are associated with hallucinations. Mixed episode is a complex syndrome which is difficult to diagnose, has the most prolonged duration of bipolar episodes and more frequent psychotic profile than pure mania with high suicidality and poor response to drugs. Mixed state mania has been well known since Kreapelin and listed in classification systems with criteria that include both a manic and a major depressive episode nearly every day for at least a one-week period. On the other hand, mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electro-convulsive therapy or light therapy) should not contribute toward a diagnosis of Bipolar I Disorder. Although, theoretically, mania is supposed to be resolved within 1-3 months even without treatment, psychiatric hospitalization is very common in especially severe cases due to functional impairment. Current treatments for mania aim to control the agitation, impulsivity, aggression and psychotic symptoms and to help patients regain their pre-morbid functionality. However, the clinical management of mania is challenging as most patients show syndromal remission but incomplete functional recovery after the first episode of mania.     

The genetics of affective disorder and genetic counseling

Abstract

Affective disorders—depression and mania—occurring with no preexisting psychiatric condition, severe physical illness, or recent personal loss can be divided into unipolar (depression only) and bipolar (both manic and depressive episodes) disorders. Bipolar illness is transmitted in some families as an X‐linked dominant factor. In other families, X‐linked transmission does not occur. Hence, bipolar illness may be similar to retinitis pigmentosa. This makes some types of genetic counseling difficult to apply to bipolar families. There is no evidence that unipolar depressive illness is transmitted by an X‐linked factor. Family studies indicate that there might be more than one type of unipolar illness. Limited prediction of risk of depression and other psychiatric conditions in other family members can be based on family studies which show that alcoholism and personality disorder occur frequently in families of early onset depressives but much less frequently in families of late onset depressives (age 40 or older).     

Associations of Serum Cytokine Receptor Levels with Melancholia,Staging of Illness,Depressive and Manic Phases,and Severity of Depression in Bipolar Disorder

To examine cytokine receptor biomarkers in bipolar disorder (BD), we recruited 133 well-phenotyped BD patients and 50 normal controls and measured serum levels of soluble interleukin 1 receptor antagonist (sIL-1RA), soluble interleukin-2 receptor (sIL-2R), sIL-6R, and tumor necrosis factor receptor 60 and 80 kDa (sTNFR60/80). sIL-1RA and sTNFR80 are significantly higher in BD than in controls and sTNFR80 and higher in melancholic than in non-melancholic patients and controls. Kapczinski’s stages 3 + 4 are characterized by lowered sIL-2R and increased sTNFR80 levels. Acute phase depression is characterized by increased sTNFR80 levels as compared with controls, manic, and euthymic patients. Both sTNFR60 and sTNFR80 levels are significantly and positively related with severity of depression but not mania. Logistic regression analysis showed that the significant predictors for BD are increased sIL-1RA levels, nicotine dependence and a family history of depression and alcoholism. The risk factors for stages 3 + 4 are lowered sIL-2R levels and nicotine dependence. Melancholia is predicted by higher sTNFR80 levels and female sex. Severity of depression is predicted by female sex, nicotine dependence, and increased sTNFR60 and sTNFR80 levels. Cell-mediated immunity is activated during a current episode of depression but not (hypo)mania or the euthymic state. There are no associations between the biomarkers and age at onset, duration of illness, severity of mania, bipolar (BP)2 or BP1 subtypes, rapid cycling, atypical depression, psychotic or suicidal symptoms, and a family history of psychiatric disease. The results show that increased sIL-1RA may be a trait marker of BD, increased sTNFR80 a state marker of the depressive phase, especially melancholia, while lower sIL-2R but higher sTNFR80 may be staging biomarkers.     

Effects of Age,Sex, Index Admission,and Predominant Polarity on the Seasonality of Acute Admissions For Bipolar Disorder: A Population-Based Study

Bipolar disorder seasonality has been documented previously, though information on the effect of demographic and clinical variables on seasonal patterns is scant. This study examined effects of age, sex, index admission, and predominant polarity on bipolar disorder seasonality in a nationwide population. An inpatient cohort admitted to hospital exclusively for mental illness was derived from the Taiwan National Health Insurance Research Database for 2002–2007. The authors identified 9619 inpatients with bipolar disorder, who had generated 15 078 acute admission records. An empirical mode decomposition method was used to identify seasonal oscillations in bipolar admission data, and regression and cross-correlation analyses were used to quantify the degree and timing of bipolar admission seasonality. Results for seasonality timing found that manic or mixed episodes peak in spring or summer, and depressive episodes peak in winter. Analysis for degree of seasonality revealed that (1) the polarity of patients' index admission predicted the seasonality of relapse admissions; (2) seasonality was significant in female admissions for depressive episodes and in male admissions for manic episodes; (3) young adults displayed a higher degree of seasonality for acute admissions than middle-aged adults; and (4) patients with predominantly depressive admissions displayed a higher degree of seasonality than patients with predominantly manic admissions. Demographic and clinical variables were found to affect the seasonality of acute admissions for bipolar disorders. These findings highlight the need for research on identification and management of seasonal features in bipolar patients. (Author correspondence: ccyang@physionet.org)     

Altered Regional Homogeneity in Pediatric Bipolar Disorder during Manic State: A Resting-State fMRI Study

Pediatric bipolar disorder (PBD) is a severely debilitating illness, which is characterized by episodes of mania and depression separated by periods of remission. Previous fMRI studies investigating PBD were mainly task-related. However, little is known about the abnormalities in PBD, especially during resting state. Resting state brain activity measured by fMRI might help to explore neurobiological biomarkers of the disorder. Methods: Regional homogeneity (ReHo) was examined with resting-state fMRI (RS-fMRI) on 15 patients with PBD in manic state, with 15 age-and sex-matched healthy youth subjects as controls. Results: Compared with the healthy controls, the patients with PBD showed altered ReHo in the cortical and subcortical structures. The ReHo measurement of the PBD group was negatively correlated with the score of Young Mania Rating Scale (YMRS) in the superior frontal gyrus. Positive correlations between the ReHo measurement and the score of YMRS were found in the hippocampus and the anterior cingulate cortex in the PBD group. Conclusions: Altered regional brain activity is present in patients with PBD during manic state. This study presents new evidence for abnormal ventral-affective and dorsal-cognitive circuits in PBD during resting state and may add fresh insights into the pathophysiological mechanisms underlying PBD.     

Gender differences in psychotic bipolar mania

Objective: This study examined gender differences in the prevalence and types of psychotic symptoms in bipolar mania.Methods: Participants were drawn from consecutive admissions to the psychiatric clinic in Chemnitz, Germany, in 2005. The diagnosis of bipolar disorder, manic episode was made within 24 hours of admission, and the severity of mania was assessed using the Young Mania Rating Scale (YMRS) and the German version of the Altman Self-Rating Mania Scale. Data collected for each patient included age at the onset of bipolar illness, number of previous episodes, social functioning between episodes, and duration of hospitalization for the index episode. Based on the Task Force for Methods and Documentation in Psychiatry system, psychotic symptoms were classified as hallucinations (visual, auditory, olfactory, tactile, acousma, somatic); delusions (paranoid, reference, guilt, grandeur, religious, erotomania, hypochondriac, poverty, jealousy); and ego disorder (thought control, thought broadcasting).Results: One hundred thirty-seven women and 109 men met the criteria for an acute manic episode, of whom 93 women and 62 men had psychotic symptoms. Compared with psychotic men, psychotic women had more delusions and hallucinations, both overall and per patient, and more delusions of reference and paranoid delusions. Psychotic women had more mixed states compared with psychotic men. Psychotic women differed from both psychotic men and nonpsychotic women on a number of clinical and social variables: they had higher YMRS scores and more previous episodes of depression despite an earlier onset of illness.Conclusion: Women with bipolar mania exhibited a specific pattern of psychotic symptoms that appeared to be associated with greater severity of the acute episode, more mixed states, and a more severe course of illness.     

Evaluation of plasma antioxidant levels during different phases of illness in adult patients with bipolar disorder

The aim of the present study is to evaluate role of plasma antioxidants (albumin, bilirubin and uric acid) in patients suffering from type I Bipolar Disorder (BD-I) during different phases of illness: acute mania, euthymia and bipolar depression. Medical records of consecutive 110 BD-I patients (38 patients with acute mania, 35 in euthymic state, full remission, and 37 in depressive phase) were reviewed to evaluate plasma antioxidant levels. Laboratory data of 40 healthy controls were also obtained. The scores of Young Mania Rating Scale (YMRS), Bech-Rafaelsen Manic Rating Scale (BRMRS) and Hamilton Rating Scale for Depression (HAM-D) were evaluated. Serum uric acid levels were higher in acute mania than other patient subgroups and healthy controls. Serum uric acid levels directly correlated with BRMRS and YMRS scores. No differences were found between clinical groups during different phases and healthy controls concerning albumin and bilirubin. In conclusion, the results of the present study support the notion that serum uric acid levels may be higher in patients with BP-I (especially during manic phases) which may suggest a dysregulation of the purinergic system. However, limitations should be considered and further studies are needed.     

Les médicaments thymorégulateurs et leurs associations dans le traitement des troubles bipolaires

Mood stabilizers are defined by their effectiveness on the various clinical aspects of bipolar episodes (mania, hypomania, depression, mixed states, rapid cycling etc.), and prophylaxis in the long-term course of the disorder. Only a few molecules have a proven efficacy to prevent or limit these disturbances: lithium, carbamazepine, valproic acid, lamotrigine and atypical antipsychotics. In clinical practice polypharmacy is the rule. We have to consider the rationale of these associations.     

The switch mechanism in periodic catatonia and manic-depressive disorder.

Both in periodic catatonia and in manic-depressive disorders sudden switches occur in behavior, in the autonomic nervous system and in the catecholamine metabolism during the transition from interval or depression into catatonia or mania. Both the manic and the catatonic attacks seem to be superimposed on the basic depressive or schizophrenic illnesses. The attacks can be counteracted or suppressed by psychotropic drugs such as alpha-methyldopa, disulfiram, reserpine, haloperidol or chloropromazine which interfere with the catecholamine metabolism or their receptor sites. The involvement of the catecholamines may however be secondary to primary defects in the thyroid, the hypothalamus or the limbic system. The strict periodicity in periodic catatonia points to an accumulation of some active metabolite which may be produced centrally during the interval. At a certain level it may trigger the switch-mechanism and then be reduced during the catatonic phase. In periodic catatonia both the basic schizophrenic disease as well as the periodic manifestations are compensated by thyroxine-thyroid treatment.     

Human Borna disease virus-infection and its therapy in affective disorders

Patients with affective disorders show an enhanced prevalence of Borna disease virus (BDV)-infection. Furthermore, BDV causes latent infection preferably in limbic central nervous structures and is suggested to be causally related to subtypes of affective disorders, especially with melancholic clinical features or bipolarity. Such a possible link was highlighted by the first report of amantadine showing an antidepressive and an antiviral efficacy against BDV in a patient with a bipolar disorder. This article summarizes clinical studies which followed this first report on the use of amantadine in BDV-infected patients with an affective disorder. A special focus is given on an open clinical study in patients with depression (n = 25), a study in remitted patients with affective disorders (n = 16), and the effect of amantadine on severe hypomanic or moderately manic patients with a bipolar disorder in an on-off-on study. In these studies amantadine reduced clinical symptoms paralleled by a reduction of BDV-infection in depressive patients, it also reduced all three BDV-parameters (BDV-Ab, -AG, and -CICs) in remitted patients, and it even reduced severe hypomania and moderate mania in bipolar patients. These data suggest the existence of an etiopathogenetic link between BDV and subtypes of affective disorders.     

Predictors of the Onset of Manic Symptoms and a (Hypo)Manic Episode in Patients with Major Depressive Disorder

Objective

One third of patients with a major depressive episode also experience manic symptoms or, even, a (hypo)manic episode. Retrospective studies on the temporal sequencing of symptomatology suggest that the majority of these patients report depressive symptoms before the onset of manic symptoms. However, prospective studies are scarce and this study will, therefore, prospectively examine the onset of either manic symptoms or a (hypo)manic episode in patients with a major depressive disorder. In addition, we will consider the impact of a large set of potential risk factors on both outcomes.

Methodology

Four-year follow-up data were used to determine the onset of manic symptoms as well as a CIDI-based (hypo)manic episode in a large sample (n = 889, age: 18–65 years) of outpatients with a major depressive disorder and without manic symptoms at baseline. Baseline vulnerability (i.e., sociodemographics, family history of depression, childhood trauma, life-events) and clinical (i.e., isolated manic symptoms, depression characteristics, and psychiatric comorbidity) factors were considered as potential risk factors.

Results

In our sample of depressed patients, 15.9% developed manic symptoms and an additional 4.7% developed a (hypo)manic episode during four years. Baseline isolated manic symptoms and comorbid alcohol dependence predicted both the onset of manic symptoms and a (hypo)manic episode. Low education only predicted the onset of manic symptoms, whereas male gender, childhood trauma and severity of depressive symptoms showed strong associations with, especially, the onset of (hypo)manic episodes.

Conclusions

A substantial proportion (20.6%) of patients with a major depressive disorder later developed manic symptoms or a (hypo)manic episode. Interestingly, some identified risk factors differed for the two outcomes, which may indicate that pathways leading to the onset of manic symptoms or a (hypo)manic episode might be different. Our findings indirectly support a clinical staging model.     

Psychotic mania in glucose-6-phosphate-dehydrogenase-deficient subjects

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with acute psychosis, catatonic schizophrenia, and bipolar disorders by previous inconclusive reports. A particularly disproportionate rate of enzyme deficiency was found in manic schizoaffective patients from 662 lithium patients surveyed in Sardinia. The purpose of this study was to describe clinical characteristics which may be potentially associated with G6PD deficiency. METHODS: Characteristics of episodes, course of illness, family pattern of illness, laboratory tests, and treatment response of 29 G6PD-deficient subjects with a Research Diagnostic Criteria diagnosis of manic schizoaffective disorder were abstracted from available records. RESULTS: The most peculiar pattern was that of acute recurrent psychotic manic episodes, mostly characterized by loosening of associations, agitation, catatonic symptoms, and/or transient confusion, concurrent hyperbilirubinemia, positive psychiatric family history, and partial response to long-term lithium treatment. CONCLUSIONS: A relationship between psychiatric disorder and G6PD deficiency is to be searched in the bipolar spectrum, particularly among patients with a history of acute episodes with psychotic and/or catatonic symptoms or with transient confusion.     

Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent

Cortical oscillations play a fundamental role in organizing large-scale functional brain networks. Noninvasive brain stimulation with temporally patterned waveforms such as repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) have been proposed to modulate these oscillations. Thus, these stimulation modalities represent promising new approaches for the treatment of psychiatric illnesses in which these oscillations are impaired. However, the mechanism by which periodic brain stimulation alters endogenous oscillation dynamics is debated and appears to depend on brain state. Here, we demonstrate with a static model and a neural oscillator model that recurrent excitation in the thalamo-cortical circuit, together with recruitment of cortico-cortical connections, can explain the enhancement of oscillations by brain stimulation as a function of brain state. We then performed concurrent invasive recording and stimulation of the human cortical surface to elucidate the response of cortical oscillations to periodic stimulation and support the findings from the computational models. We found that (1) stimulation enhanced the targeted oscillation power, (2) this enhancement outlasted stimulation, and (3) the effect of stimulation depended on behavioral state. Together, our results show successful target engagement of oscillations by periodic brain stimulation and highlight the role of nonlinear interaction between endogenous network oscillations and stimulation. These mechanistic insights will contribute to the design of adaptive, more targeted stimulation paradigms.     

Gender Differences in Neuropsychological Performance across Psychotic Disorders – a Multi-Centre Population Based Case-Control Study

Background

Patients with schizophrenia and other psychoses exhibit a wide range of neuropsychological deficits. An unresolved question concerns whether there are gender differences in cognitive performance.

Methods

Data were derived from a multi-centre population based case-control study of patients with first-episode psychosis. A neuropsychological test battery was administered to patients with a diagnosis of schizophrenia or schizoaffective disorder (N=70, 36% females), bipolar/mania (N=34, 60% females), depressive psychosis (N=36, 58% females) and healthy controls (N=148, 55% females). Generalized and specific cognitive deficits were compared.

Results

There was strong evidence for disorder-specific gender differences in neuropsychological performance. Males and females with schizophrenia showed similar pervasive neuropsychological impairments. In psychotic depressive disorder females performed worse than males across neuropsychological measures. Differences in neuropsychological performance between males and females with bipolar/manic disorder were restricted to language functions. Symptom severity did not contribute to the observed gender differences.

Conclusions

Early in the course of psychotic illness, gender related factors appear to moderate the severity of cognitive deficits in depressive psychosis and bipolar/mania patients.     

Bipolar manic-depressive psychoses: Results of a genetic investigation

Summary Ninety-five patients with bipolar manicdepressive disorders were followed from 1959 to 1975, and their first-degree relatives (N=617) were studied. In the search for heterogeneity of bipolar illness the patients were subclassified according to various criteria: sex, age at onset, number of episodes, and longitudinal syndrome subtypes (Dm, MD, Md), and the genetic findings were used as an external criterion.The first-degree relatives of female probands showed a higher morbidity risk for psychiatric disorders than the relatives of male probands, and the highest morbidity risk was found in the female relatives of female probands. Early onset and late-onset patients did not differ from a genetic point of view. Patients with ten episodes or more showed slightly higher family morbidity than those with less than ten episodes.The three subtypes of bipolar disorders preponderantly depressed (Dm), nuclear type (MD), and preponderantly manic (Md), showed significant genetic differences. The families of type Dm had the highest morbidity, and families of type Md, the lowest! The type MD took an intermediate position. The results are surprising and not compatible with current hypotheses of multifactorial heredity assuming a continuum from depression to mania with distinct thresholds for the manifestation of unipolar depression, bipolar psychosis, and pure mania. The findings also do not suggest the existence of a drug-induced hypomania.Father-son transmission was frequent, and this fact excludes a substantial amount of X-chromosomal inheritance.Parents, siblings, and children exhibited roughly the same morbidity risk. If a proband had an affected parent, the morbidity risk for his siblings and children was nearly twice as high as without such a parent (38% vs 21%). The analysis of the intrafamilial distribution of diagnoses supported the assumption that neurotic depression belongs to the true spectrum of affective psychoses.     

Mitochondrial Dysfunction and Psychiatric Disorders

Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells. Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders. Tissues with high energy demands, such as the brain, contain a large number of mitochondria, being therefore more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients and after amphetamine administration, an animal model of mania. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Schizophrenia is a devastating mental disorder characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets. Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals. Considering that several studies link energy impairment to neuronal death, neurodegeneration and disease, this review article discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders, like bipolar disorder, depression and schizophrenia.     

Maintenance treatment of bipolar disorders

Conventional antipsychotic drugs, although efficacious in the treatment of mania, have not demonstrated a significant usefulness in the maintenance treatment of bipolar disorder. This has primarily been due to a tendency to induce depressive symptoms and depressive recurrences in this group of patients in the course of long-term administration. However, the picture has changed following the introduction of second-generation antipsychotics. These drugs have pro-depressant properties (if any) that are much weaker than conventional antipsychotics. Furthermore, their tolerability, especially in long-term treatment, is more favorable compared to classical antipsychotics. Clinical observations of the action profile of second-generation antipsychotic drugs in the treatment of schizophrenia have pointed to a possibility of these agents possessing mood-stabilizing properties. The first such suggestion was made by Zarate (1995) in connection with clozapine. The prevention of manic and depressive recurrences in bipolar disorder is a hallmark of the definition of mood-stabilizers.     

Critical slowing down as an early warning of transitions in episodes of bipolar disorder: A simulation study based on a computational model of circadian activity rhythms

Bipolar disorder is characterized by repeated episodes of mania and depression, and can be understood as pathological complex system behaviour involving cognitive, affective and psychomotor disturbance. Accurate prediction of episode transitions in the long-term pattern of mood changes in bipolar disorder could improve the management of the disorder by providing an objective early warning of relapse. In particular, circadian activity changes measured via actigraphy may contain clinically relevant signals of imminent systemic dysregulation. In this study, we propose a mathematical index to investigate the correlation between apparently irregular circadian activity rhythms and critical transitions in episodes of bipolar disorder. Not only does the proposed index illuminate the effects of pharmacological and psychological therapies in control over the state, but it also provides a framework to understand the dynamic (or state-dependent) control strategies. Modelling analyses using our new approach suggest that key clinical goals are minimizing side effects of mood stabilizers as well as increasing the efficiency of other therapeutic strategies.