Mixed States In Bipolar Disorder Research Articles

Mixed states in bipolar disorder: the role of depressive and hypo/manic symptoms in suicidal ideation

Mixed states in bipolar disorder: the role of depressive and hypo/manic symptoms in suicidal ideation

Vocal features obtained through automated methods in verbal fluency tasks can aid the identification of mixed episodes in bipolar disorder

There is a lack of consensus on the diagnostic thresholds that could improve the detection accuracy of bipolar mixed episodes in clinical settings. Some studies have shown that voice features could be reliable biomarkers of manic and depressive episodes compared to euthymic states, but none thus far have investigated whether they could aid the distinction between mixed and non-mixed acute bipolar episodes. Here we investigated whether vocal features acquired via verbal fluency tasks could accurately classify mixed states in bipolar disorder using machine learning methods. Fifty-six patients with bipolar disorder were recruited during an acute episode (19 hypomanic, 8 mixed hypomanic, 17 with mixed depression, 12 with depression). Nine different trials belonging to four conditions of verbal fluency tasks—letter, semantic, free word generation, and associational fluency—were administered. Spectral and prosodic features in three conditions were selected for the classification algorithm. Using the leave-one-subject-out (LOSO) strategy to train the classifier, we calculated the accuracy rate, the F1 score, and the Matthews correlation coefficient (MCC). For depression versus mixed depression, the accuracy and F1 scores were high, i.e., respectively 0.83 and 0.86, and the MCC was of 0.64. For hypomania versus mixed hypomania, accuracy and F1 scores were also high, i.e., 0.86 and 0.75, respectively, and the MCC was of 0.57. Given the high rates of correctly classified subjects, vocal features quickly acquired via verbal fluency tasks seem to be reliable biomarkers that could be easily implemented in clinical settings to improve diagnostic accuracy.

Tracing the psychopathology of bipolar disorder to the functional architecture of intrinsic brain activity and its neurotransmitter modulation: a three-dimensional model.

Bipolar disorder (BD) shows complex alterations in psychomotor, affective, and thought dimensions, as described by Kraepelin in his fundamental model of manic-depressive illness. In turn, the expression of behavioral/phenomenological dimensions is traceable to intrinsic brain activity. We reported a data overview on intrinsic brain functioning and its changes in BD. Accordingly, we proposed a three-dimensional model of the relationship between brain functioning and behavioral/phenomenological patterns, along with its application to BD. In this model, intrinsic brain activity is organized in distinct units in accordance to connectivity patterns and related setting of input/output processing, underlying the different behavioral/phenomenological dimensions. An external unit (mainly involving the sensorimotor network) is connected with the external environment and sets the exteroceptive input/somatomotor output processing, underlying the psychomotor dimension. An internal unit (mainly involving the salience network) is connected to the internal/body environment and sets the interoceptive input/visceromotor output processing, underlying the affective dimension. Finally, an associative unit (mainly involving the default-mode network) is not connected with the environment and sets the processing of associative inputs/outputs, underlying the thought dimension. In each unit, neurotransmitter signaling couples the subcortical-cortical loop, which modulates the network activity levels, in turn setting input/output processing and related expression levels of the behavioral/phenomenological dimension. Different combinations in neurotransmitter signaling favor network balancing into distinct functional brain states, which manifest in different combinations of excitation or inhibition in psychomotricity, affectivity, and thought, resulting in the manic, depressive, and mixed states of BD. Our working model might provide a coherent framework for tracing the complex BD psychopathology to core functional brain alterations.

Mixed states and suicidal behavior: a systematic review.

The objective of this study was to identify whether mixed states in bipolar disorder (BD) are associated with more frequent suicidal behavior when compared to manic/hypomanic and depressive episodes. We performed a systematic search of the scientific literature on the subject using the PubMed, ISI Web Of Science, PsycINFO and SciELO databases. The terms chosen for the search were (bipolar) AND (suicid*) AND (mixed). We selected original studies comparing suicidal behavior of patients in mixed states and suicidal behavior of patients in other BD phases. Sixteen papers fit the selection criteria. Twelve of the original 16 studies compared suicidal behavior in mixed states and pure mania, and the majority of these studies (n = 11) revealed that suicidal behavior was more frequent among individuals in mixed states. Five of the papers compared suicidal behavior between depressive and mixed phases of BD. One of these five papers reported more severe suicidal behavior in patients in mixed states and another described more frequent suicidal behavior in patients with pure depression. There were no significant statistical differences between groups in the remaining three of these five studies. During acute BD episodes, suicidal behavior is more strongly associated with mixed states than with pure mania or hypomania. However, it was not possible to demonstrate that the association between suicidal behavior and mixed states is stronger than the association between suicidal behavior and depressive phases. The results hereby presented are worth considering in clinical practice to better evaluate suicide risk and to prevent suicide.

Effect of mood on serum osmolarity: a comparison between manic, depressive and mixed states of bipolar disorder

Effect of mood on serum osmolarity: a comparison between manic, depressive and mixed states of bipolar disorder

Mixed states in bipolar disorder: modelling, measuring and managing.

To consider whether consensus exists in recommendations for managing bipolar mixed states published in recent reviews and treatment guidelines, and to summarise what might be their best management. Limitations to and changes in the definition of mixed states compromise diagnosis and management. The striking comparison between DSM-IV and DSM-5 criteria sets risks under-diagnosis and over-diagnosis. Current reviews and guidelines offer limited evidence to guide treatment; however, management should involve addressing the contribution of any antidepressant medication, and the introduction of a second-generation antipsychotic medication to stabilise the condition.

Modeling of Hansen's solubility parameters of aripiprazole, ziprasidone, and their impurities: A nonparametric comparison of models for prediction of drug absorption sites

AbstractAripiprazole and ziprasidone are atypical antipsychotic drugs with the effect on positive and negative symptoms of schizophrenia, mania, and mixed states of bipolar disorder. Hansen's solubility parameters, δd, δp, and δh, which account for dispersive, polarizable, and hydrogen bonding contributions to the overall cohesive energy of a compound, are often used to assess pharmacokinetic properties of drugs. However, no data exist of solubility parameters for the drugs of interest in this study. Therefore, in the present study, partial least square regression (PLS), artificial neural networks (ANNs), regression trees (RT), boosted trees (BT), and random forests (RF) were applied to estimate Hansen's solubility parameters of ziprasidone, aripiprazole, and their impurities/metabolic derivatives, targeting their biopharmaceutical classes and absorption routes. A training set of 47 structurally diverse and pharmacologically active compounds and 290 molecular descriptors and pharmaceutically important properties were used to build the prediction models. The modeling approaches were compared by the sum of ranking differences, using the consensus values as a reference for the unknowns and the experimentally determined values as a gold standard for the calibration set. In both instances, the PLS models, together with ANNs, demonstrated better performance than RT, BT and especially RF. Based on the best scored models, we were able to pinpoint the most probable absorption sites for each drug and the corresponding metabolite, i.e., the upper parts of the gastrointestinal tract, small intestine, or absorption along entire length of gastrointestinal tract.

Mixed States in Bipolar Disorder: Etiology, Pathogenesis and Treatment.

Many bipolar disorder patients exhibit mixed affective states, which portend a generally more severe illness course and treatment resistance. In the previous renditions of Diagnostic and Statistical Manual mixed states were narrowly defined in the context of bipolar I disorder, but with the advent of DSM-5 the term “mixed episode” was dropped and replaced by “mixed features” specifier which could be broadly applied to manic, hypomanic and depressive episodes in both the bipolar spectrum and major depressive disorders. This paradigm shift reflected their significance in the prognosis and overall management of mood disorders, so that the clinicians should thoroughly familiarize themselves with the contemporary notions surrounding these conditions. The purpose of this manuscript is to bring to light the current conceptualizations regarding the etiology, pathogenesis and treatment of mixed states. To achieve this goal, in June 2016 an extensive literature search was undertaken using the PubMed database. Some exploratory terms utilized included “mixed states”, “mixed episodes”, “switching”, “rapid cycling” cross referenced with “bipolar disorder”. Focusing on the most relevant and up to date studies, it was revealed that mixed states result from genetic susceptibility in the circadian and dopamine neurotransmission apparatuses and disturbance in the intricate catecholamine-acetylcholine neurotransmission balance which leads to mood fluctuations. The management of mixed states is challenging with atypical antipsychotics, newer anticonvulsants and electroconvulsive therapy emerging as the foremost treatment options. In conclusion, while progress has been made in the neurobiological understanding of mixed states, the currently available therapeutic modalities have only shown limited effectiveness.

Consider second-generation antipsychotics for the management of mixed states in bipolar disorder

The diagnosis and treatment of mixed states in bipolar disorder can be challenging. The mainstay of treatment is antipsychotic therapy (± a mood stabilizer), with second-generation antipsychotics emerging as the treatment of choice. When medication fails or cannot be used, electroconvulsive therapy may be effective.

The role of medical condition in perplexity inside psychotic mixed states in bipolar disorder: Case series and literature review

IntroductionIn literature Leonard introduce, after Wernike (1900) and Kleist (1928), the concept of cycloid psychoses, and he gives again a weight to the mixed forms in affective disorders [1–4]. A lot of different medical conditions cause pychiatric problems, like hyperammonemia, hyponatiremia, thyroid disfunction, urinary infections and still others. The aim of our study is to evaluate the role of a medical condition in perplexity inside psychotic mixed states in bipolar disorder (BD). We propouse three different cases and literature review.MethodThree patients with perplexity in BD were assessed with: the SCID-P for axis I diagnosis, HRSD, YMRS, internistical examination, blood test exams and urinanalysis, and first level brain imagin (CT and/or MRI). We conducted a systematic review of the literature (PubMed, Embase, PsychInfo), using the terms “bipolar disorder”, “mixed states”, “perplexity” and “medical condition”.ResultsAll our patients present: hyperammonemia, reduction of TSH and presence of infection at the urinanalysis, and a resolution of perplexity with the normalization of the blood test and urinanalysis.Discussion and conclusionTo our knowledge there are not studies that confirm the relationship between thyroid and epatic dysfunction, and urinary infection with perplexity in psychotic mixed states in BD, and the resolution with the normalization of blood and urinary exams. Further research is warranted to replicate our clinical observations and to confirm our results.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Diagnosis, Epidemiology and Management of Mixed States in Bipolar Disorder.

Approximately 40% of patients with bipolar disorder experience mixed episodes, defined as a manic state with depressive features, or manic symptoms in a patient with bipolar depression. Compared with bipolar patients without mixed features, patients with bipolar mixed states generally have more severe symptomatology, more lifetime episodes of illness, worse clinical outcomes and higher rates of comorbidities, and thus present a significant clinical challenge. Most clinical trials have investigated second-generation neuroleptic monotherapy, monotherapy with anticonvulsants or lithium, combination therapy, and electroconvulsive therapy (ECT). Neuroleptic drugs are often used alone or in combination with anticonvulsants or lithium for preventive treatment, and ECT is an effective treatment for mixed manic episodes in situations where medication fails or cannot be used. Common antidepressants have been shown to worsen mania symptoms during mixed episodes without necessarily improving depressive symptoms; thus, they are not recommended during mixed episodes. A greater understanding of pathophysiological processes in bipolar disorder is now required to provide a more accurate diagnosis and new personalised treatment approaches. Targeted, specific treatments developed through a greater understanding of bipolar disorder pathophysiology, capable of affecting the underlying disease processes, could well prove to be more effective, faster acting, and better tolerated than existing therapies, therefore providing better outcomes for individuals affected by bipolar disorder. Until such time as targeted agents are available, second-generation neuroleptics are emerging as the treatment of choice in the management of mixed states in bipolar disorder.

Neuroinflammation and excitatory symptoms in bipolar disorder

Neuroinflammation has been proposed as a strong biological factor underlying the development of neuropsychiatric diseases. A role for dysregulation of the immune system was initially suggested in depressive disorders and subsequently extended to other illnesses, including bipolar disorder (BD). Indeed, there is growing evidence confirming the presence of a generalized pro-inflammatory state in BD patients, involving alterations in cytokine, acute-phase proteins, and complement factor secretion, white blood cell differentiation, microglial activation, arachidonic acid signaling pathways, and increased oxidative stress markers. Medications commonly used to treat BD, such as lithium, antiepileptics and antipsychotics, show some immunoregulatory activity both in vitro and in vivo. The aim of our study was to review the role of different inflammatory mechanisms, specifically in the development of excitatory symptoms, via a systematic PubMed search of the literature. Despite the high variability of results among studies, we found evidence indicating specific alterations of the inflammatory response during manic and mixed states of BD. These findings may help to clarify some of the complex mechanisms underlying the development of excitatory symptoms and suggest a potential role for drugs targeting the inflammatory system as new therapeutic options.

Decreased plasma levels of brain-derived neurotrophic factor (BDNF) during mixed episodes of bipolar disorder

BackgroundBrain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and neuroplasticity. Decreased blood levels of BDNF have been found during acute manic and depressive states. BDNF has been proposed as a biomarker in illness phases of mood disorders. No information is available regarding BDNF levels during the mixed states of bipolar disorder (BD). The aim of this study was to evaluate BDNF levels during mixed episodes of BD patients and compare them with those of healthy subjects and depressed patients. MethodsPlasma BDNF levels were measured by an ELISA assay in 18 patients with major depressive episode (MDE), 19 patients with mixed episode (ME) and 15 healthy subjects (HS). ResultsBDNF levels were significantly higher in HS, as compared with patients׳ samples (HS vs. MDE patients: p<001; HS vs. ME patients: p=.022). No significant differences were found between BDNF levels of ME and MDE patients. The severity of illness as assessed by CGI-S was significantly higher in ME than in MDE patients (p=.01). LimitationsThe small sample size may have weakened the power of statistical analyses. All patients received mood-stabilizing and antidepressant treatments which have been reported to influence peripheral BDNF levels. ConclusionsOur results are consistent with previous studies showing reduced BDNF during both manic and depressive episodes. This finding supports the role of BDNF as a state-marker of mood episodes, and may represent a contribution to a unitary approach model between unipolar and BDs, as well as to the manic-depressive spectrum model.

Emotional hyperreactivity as a core dimension of manic and mixed states

Despite its obvious importance in mood disorders, characterization of emotional reactivity has been neglected in bipolar disorders. Concerning manic states and the current classification, the main criterion is the presence of an elevated or expansive mood. In contrast to this characteristic and often prolonged mood state, emotional reactivity refers to a brief evoked response to salient emotional stimuli. The goal of this study was to assess the intensity of emotional responses triggered by viewing slides in bipolar patients with manic or mixed states. Our hypothesis was that all emotional responses are exacerbated, whatever the valence of the stimuli. We compared 33 patients with manic or mixed states with 33 matched euthymic patients and 33 healthy control subjects. Arousal and attribution of valence were assessed while subjects viewed slides taken from the International Affective Picture System (positive, neutral and negative slides). Patients with manic or mixed states reported a higher arousal when viewing all types of slides in comparison with the other groups. Concerning attribution of valence, patients with manic or mixed states assessed neutral slides as more pleasant. When bipolar patients with manic and mixed states are placed in front of positive, neutral and negative slides, the slides trigger a higher intensity of emotions, whatever the valence of the emotional stimuli. These results strengthen the importance of emotional hyperreactivity as a core dimension in manic and mixed states in bipolar disorder.

Add-on Lamotrigine Treatment for Subsyndromal Depression after Manic or Mixed States in Bipolar Disorder Improved the Quality of Life

Two cases of patients experienced subsyndromal depression after manic or mixed hypomanic and depressive episodes due to bipolar I (case 1) and II (case 2) disorders prior to the use of lamotrigine. Case 1 showed episodes of mood switching induced by antidepressants and seasonal mood instability. Case 2 showed hippocampal atrophy and a persistent dull headache that preceded the use of lamotrigine. Both were successfully treated with add-on lamotrigine therapy, and the dull headache was effectively treated with olanzapine. Both patients improved in social activity and work performance after these add-on treatments. Thus, add-on treatment with lamotrigine alone or in combination with olanzapine was an effective strategy to improve the quality of life in bipolar depression. Subsyndromal depression that present after the disappearance of the manic or mixed state was suggested to be practical indication for the use of lamotrigine.

Review of the safety, efficacy, and side effect profile of asenapine in the treatment of bipolar 1 disorder

Objective:Asenapine is approved for acute manic and mixed states in bipolar disorder. The objective is to review the efficacy of asenapine in bipolar disorder, with a particular focus on acceptability and adherence to treatment.Methods:Five clinical trials were conducted in bipolar disorder manic or mixed states: two 3-week trials (n = 976) comparing asenapine to placebo, a 9-week extension (n = 504), and a 40-week extension (n = 107). One trial was conducted comparing asenapine to placebo (n = 326) as adjunctive therapy for subjects with an incomplete response to lithium or valproate. All trials were conducted in the USA and internationally.Results:Asenapine was found to be efficacious for manic and mixed states in bipolar disorder compared with placebo control, and compares equally well to olanzapine on efficacy measures after 3 weeks of treatment. Asenapine was not found to be efficacious for depression symptoms. Common asenapine side effects in the 40-week extension trial were sedation, insomnia, and dizziness, and 31% reported clinically significant weight gain, compared with 55% reporting clinically significant weight gain with olanzapine. Additionally, 18% had clinically significant changes in fasting blood glucose levels compared to 22% of those on olanzapine. In terms of patient acceptability, one concern may be sublingual administration requiring no liquids or food for 10 minutes after dosing and a twice-daily regimen. Suggestions about addressing barriers to adherence and acceptability are provided.Conclusion:Asenapine is a promising new medication in bipolar disorder. Asenapine in the long-term has a more favorable weight gain profile compared to olanzapine. No benefit was seen for depression symptoms, a major patient-reported concern. Some side effects do not remit after the short-term trials in at least 10% of patients.

A novel scale for measuring mixed states in bipolar disorder

Conventional descriptions of bipolar disorder tend to treat the mixed state as something of an afterthought. There is no scale that specifically measures the phenomena of the mixed state. This study aimed to test a novel scale for mixed state in a clinical and community population of bipolar patients. The scale included clinically relevant symptoms of both mania and depression in a bivariate scale. Recovered respondents were asked to recall their last manic episode. The scale allowed endorsement of one or more of the manic and depressive symptoms. Internal consistency analyses were carried out using Cronbach alpha. Factor analysis was carried out using a standard Principal Components Analysis followed by Varimax Rotation. A confirmatory factor analytic method was used to validate the scale structure in a representative clinical sample. The reliability analysis gave a Cronbach alpha value of 0.950, with a range of corrected-item-total-scale correlations from 0.546 (weight change) to 0.830 (mood). The factor analysis revealed a two-factor solution for the manic and depressed items which accounted for 61.2% of the variance in the data. Factor 1 represented physical activity, verbal activity, thought processes and mood. Factor 2 represented eating habits, weight change, passage of time and pain sensitivity. This novel scale appears to capture the key features of mixed states. The two-factor solution fits well with previous models of bipolar disorder and concurs with the view that mixed states may be more than the sum of their parts.

Pharmacologic treatment of rapid cycling and mixed states in bipolar disorder: an argument for the use of lithium

Lithium has long been considered as less than ideal in the management of rapid cycling and mixed states in bipolar disorder. However, these forms of bipolarity represent a generally more difficult phase of the illness to treat with any medication. Increasing knowledge about lithium's other beneficial effects, including protection against suicide and neuromodulatory effects which may protect the brain, make it a first-line treatment for any form of bipolar disorder. As newer therapies become available or receive further exploration, we should look to the past and re-embrace lithium as a core therapeutic modality for bipolarity as we move forward in the field, particularly for forms of the disorder such as rapid cycling and mixed states, historically thought to be more treatment resistant.

Electroconvulsive therapy in the treatment of mixed states in bipolar disorder

Introduction. Mixed bipolar states are not infrequent and may be extremely difficult to treat. Lithium, anticonvulsants including valproate and carbamazepine, and antipsychotics such as olanzapine, ziprasidone, and aripiprazole have been reported to be at least partially effective in controlled clinical trials, but many patients do not respond to pharmacological approaches. Electroconvulsive therapy has been tested to be efficacious for the treatment of both manic and depressive episodes, but much less evidence is available with regards to mixed states. The aim of the review was to report the available evidence for the use of electroconvulsive therapy in mixed bipolar states.Methods. A systematic review of the literature on treatment of mixed states, focused on electroconvulsive therapy, was made, beginning in August 1992 and ending in March 2007. The key words were “electroconvulsive therapy” and “mixed bipolar”.Results. Only three studies met the required quality criteria and were included. This literature suggests that ECT is an effective, safe, and probably underutilized treatment of mixed states. Recent technical developments have made ECT more friendly, tolerable, and safe. Potential alternatives, such as vagus nerve stimulation, deep brain stimulation, or transcranial stimulation, are still far to be proved as effective as ECT.

Seasonal variation of mixed and pure episodes of bipolar disorder

Background: Although seasonal patterns of manic episodes have been reported, the seasonal variation of mixed states of bipolar disorder has received little attention. In the current report we address that concern as well as the overall seasonality of manic episodes. Methods: The seasonal pattern of 304 psychiatric hospital admissions for treatment of mixed or manic bipolar episodes over a 3-year period were analyzed employing two definitions of mixed manic states: DSM-III-R and an ROC derived definition. Results: The frequency of all manic episodes combined peaked in early spring, with a nadir in late fall. Pure manic admissions showed a similar pattern. Mixed manic admissions had a significantly different pattern, with a peak in late summer and a nadir in November. The differences between pure and mixed manic admissions were demonstrated with the use of the ROC definition for mixed states. Limitations: Effects of medications and medication non-compliance may dampen natural seasonal patterns of episodes. Conclusions: The different seasonal pattern of mixed and pure manic episodes support the separation of mixed episodes as a distinct clinical subtype.