A reevaluation of mixed depressive states from the DSM-5- TR perspective: a series of prototypical cases.

Mixed depressive states are defined by the co-presence of depressive and manic symptoms. They represent extremely variable conditions from the point of view of clinical expressiveness and are difficult to recognize, ranging from clear schizophrenic-like psychoses and pseudodemented pictures to subsyndromal psychopathology. At the basis of the extreme variability of depressive pictures with mixed features are the different combinations that depressive and manic symptoms can assume. Furthermore, the intensity of depressive symptoms and manic symptoms, combined, can be variable, a factor that contributes to making the picture even more variable. Each form of mixed depressive state therefore presents its own specific symptomatic characteristics and specific difficulties in differential diagnosis and each form requires a different therapeutic strategy. In this work we have distinguished four possible specific subtypes of mixed depressive states, describing their specific clinical presentation and the therapeutic options most supported by the literature with the aim of contributing to a better recognition of mixed depressive states, to avoid incorrect diagnoses at patient and treatments that are useless if not worsening.

G.T. MSRS On-Line Calculator Targeting the Early Diagnosis of Mixed Affective States: the Multicenter Study Project Design on the Approbation and Validity of the Three Language Versions of the Rating Scale.

BACKGROUND: Mixed affective states (MS) are often misdiagnosed by the clinicians and lead to the inappropriate treatment strategies contributing to the severe forms, poor outcome with higher rates of comorbid conditions and worse remission quality in affective and bipolar disorders, as well as to a decreased psychosocial functioning of these patients. The development of reliable tools for the MS assessments or so called the phenomenon of mixity in affective disorders, is still an unmet need of psychiatric research and clinical practice. In this paper, we present PC program "Multilingual IBM-PC on-line calculator for early diagnosis of the mixed affective states" based on the Giuseppe Tavormina Mixed States Rating Scale (G.T. MSRS) (Russian, English, Italian language versions) created by the ICERN group using programming language JavaScript, working for such operation systems (OS) as Windows, Linux, MacOs, Android, iOS, and aims to contribute to the accurate assessment of the presence and severity of the mixed states among affective disorders. SUBJECTS AND METHODS: The G.T. Mixed States Rating Scale on-line calculator consists of 11 items which evaluate various aspects of MS in patients with major depression, bipolar or recurrent depressive disorder. A total score is automatically calculated, considering the type of affective temperament according to the Akiskal's and Tavormina's schemas, thus, the specific sub-groups of MS are differentiated based on the ranges: Medium-light (2-6), Medium (7-12), and High (13-19) Mixity level. The study will enroll 330 participants during two (three months follow-up) visits (110 native speakers in each of the three languages) of both genders aged from 18 till 55 y.o. with the diagnoses of depressive episodes, major depression, bipolar or recurrent depressive disorder according to the DSM-5 criteria. Assessments will be provided by the two investigators (second one will be blinded to the G.T. MSRS results obtained by the first researcher), based on the use of DSM-5 clinical interview, Young Mania Rating Scale, Montgomery-Åsberg Depression Rating Scale, Clinical Global Impression - Severity scale (CGI-S), Clinical Global Impression - Improvement scale (CGI-I), Patient Global Impression of Change (PGIC). RESULTS: The study will assess the agreement between the diagnostic category/clinical impression and the on-line G.T. MSRS calculator use results, its test-retest reliability, and diagnosis stability for further assessment of the on-line G.T. MSRS calculator validity and clinical utility. Secondary variables will evaluate internal reliability and such statistical analyses as Cronbach's alpha, Cohen's Kappa, biserial correction, and agreement between initial and follow-up diagnoses. CONCLUSIONS: Current multicenter validation study of the on-line G.T. MSRS calculator will enhance the understanding of the mixity phenomenon and its clinical implication, aiming to improve the treatment strategies to manage the course of mental disorder, quality of life and psychosocial functioning in patients with affective (bipolar) disorders, accompanied by MS, and a clinical recommendation for the routine administration of the user-friendly on-line G.T. MSRS version in clinical practice.

Mixed Depression: A Mini-Review to Guide Clinical Practice and Future Research Developments.

The debate on mixed states (MS) has been intense for decades. However, several points remain controversial from a nosographic, diagnostic, and therapeutic point of view. The different perspectives that have emerged over the years have turned into a large, but heterogeneous, literature body. The present review aims to summarize the evidence on MS, with a particular focus on mixed depression (MxD), in order to provide a guide for clinicians and encourage the development of future research on the topic. First, we review the history of MS, focusing on their different interpretations and categorizations over the centuries. In this section, we also report alternative models to traditional nosography. Second, we describe the main clinical features of MxD and list the most reliable assessment tools. Finally, we summarize the recommendations provided by the main international guidelines for the treatment of MxD. Our review highlights that the different conceptualizations of MS and MxD, the variability of clinical pictures, and the heterogeneous response to pharmacological treatment make MxD a real challenge for clinicians. Further studies are needed to better characterize the phenotypes of patients with MxD to help clinicians in the management of this delicate condition.

The significance of mixed states in mania and depression: From the psychopathological viewpoint of Tadao Miyamoto.

This article introduces the concept proposed by the eminent second-generation Japanese psychopathologist Tadao Miyamoto in 1992 that the manic-depressive mixed state is the basic psychopathology of manic-depressive illness. When Kraepelin first established the dichotomy between schizophrenia and manic-depressive illness, mania and depression were placed in a symmetrical relationship. Now, in Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), manic-depressive illness is divided into two distinct categories: bipolar and related disorders, and depressive disorders. Miyamoto pointed out that even in the average depressed state there is a manic-depressive mixed state and listed the following findings. The depressed mood of depression is itself a major fluctuation, but is constantly subject to more or less subtle fluctuations or swaying. What occurs in association with the incessant fluctuations of mood dysphoria are restlessness, agitation, irritability, and excitement, which manifest in a unique way in combination with a depressive mood. In depressive delusions, ideations of belittlement are developed in an exaggerated manner. Miyamoto concluded that mixed states are not incidental or accessory to manic-depressive illness; on the contrary, they may form a core component of manic-depressive illness.

Mania and bipolar depression: complementing not opposing poles-a post-hoc analysis of mixed features in manic and hypomanic episodes.

BACKGROUND: Depending on the classification system used, 5-40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects. METHODS: Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups. RESULTS: Mean age of participants was 40 ± 12 years (range 18-81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic < 12, hypomanic < 21, manic < 30. Average IDS-C sum scores in manic or hypomanic states were significantly higher (p < .001) than for non-manic states. (Hypo)manic female patients were likely to show more depressive symptoms than males (p < .001). Similar results were obtained when only the core items of the YMRS or only the number of depressive symptoms were considered. Analyzing the frequency of (hypo)manic mixed states applying a proxy of the DSM-5 mixed features specifier extracted from the IDS-C, we found that almost 50% of the (hypo)manic group visits fulfilled DSM-5 mixed features specifier criteria. CONCLUSION: Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other.

Electroconvulsive Therapy (ECT) in Bipolar Disorder Patients with Ultra-Rapid Cycling and Unstable Mixed States.

Background and Objectives: Unstable mixed episodes or rapid switching between opposite affective poles within the scope of short cycles was first characterized in 1967 by S. Mentzos as complex polymorphous states with chaotic overlap of manic and depressive symptoms. Well-known examples include antidepressant-induced mania/hypomania and rapid/ultra-rapid/ultradian cycling, when clinicians observe an almost continuous mixed state with a constant change of preponderance of manic or depressive symptoms. Achieving stable remission in these cases is challenging with almost no data on evidence-based treatment. When mood stabilizers are ineffective, electroconvulsive therapy (ECT) has been suggested. Objectives: After reviewing the evidence from available literature, this article presents our own clinical experience of ECT efficacy and tolerability in patients with ultra-rapid cycling bipolar disorder (BD) and unstable mixed states. Materials and Methods: We conducted an open, one-year observational prospective study with a "mirror image" design, including 30 patients with rapid and ultra-rapid cycling BD on long-term mood stabilizer treatment (18 received lithium carbonate, 6 on valproate and 6 on carbamazepine) with limited effectiveness. A bilateral ECT course (5-10 sessions) was prescribed for regaining mood stability. Results: ECT was very effective in 12 patients (40%) with a history of ineffective mood stabilizer treatment who achieved and maintained remission; all of them received lithium except for 1 patient who received carbamazepine and 2 with valproate. Nine patients (30%) showed partial response (one on carbamazepine and two on valproate) and nine patients (30%) had no improvement at all (four on carbamazepine and two on valproate). For the whole sample, the duration of affective episodes was significantly reduced from 36.05 ± 4.32 weeks in the year prior to ECT to 21.74 ± 12.14 weeks in the year post-ECT (p < 0.001). Depressive episodes with mixed and/or catatonic features according to DSM-5 specifiers were associated with a better acute ECT response and/or long-term mood stabilizer treatment outcome after ECT. Conclusions: ECT could be considered as a useful option for getting mood instability under control in rapid and ultra-rapid cycling bipolar patients. Further randomized trials are needed to confirm these results.

Pattern of occurrence of obsessive-compulsive symptoms in bipolar disorder.

Apparent comorbidity between Bipolar Disorder (BD) and Obsessive-Compulsive Disorder (OCD) is a common condition, but its meaning has not been clarified yet. The present study aimed to evaluate the pattern of occurrence of obsessive-compulsive symptoms (OCS) in the different phases of BD. One hundred and sixty-five BD patients, 62 (37.5%) euthymic, 34 (20.6%) in hypomanic/manic phase, 43 (26%) in depressive phase and 26 (15.7%) in mixed state, were assessed with the Yale-Brown Obsessive-Compulsive Scale (YBOCS), the Hamilton Depression Rating Scale (HAM-D), the Young Mania Rating Scale (YMRS) and the Ruminative Response Scale (RRS). In the whole sample, the severity of OCS was associated to the severity of depressive symptoms. The highest severity of OCS (YBOCS total score) was observed in the mixed group and the lowest scores in the hypomanic/manic group. Our findings suggest that OCS in BD patients appear as a state-dependent phenomenon cycling with the mood phases, particularly exacerbating in the context of depressive and mixed states.

Predictors of Treatment Resistance Across Different Clinical Subtypes of Depression: Comparison of Unipolar vs. Bipolar Cases.

OBJECTIVE: Treatment-resistant depression (TRD) and treatment-resistant bipolar depression (TRBD) poses a significant clinical and societal burden, relying on different operational definitions and treatment approaches. The detection of clinical predictors of resistance is elusive, soliciting clinical subtyping of the depressive episodes, which represents the goal of the present study. METHODS: A hundred and thirty-one depressed outpatients underwent psychopathological evaluation using major rating tools, including the Hamilton Rating Scale for Depression, which served for subsequent principal component analysis, followed-up by cluster analysis, with the ultimate goal to fetch different clinical subtypes of depression. RESULTS: The cluster analysis identified two clinically interpretable, yet distinctive, groups among 53 bipolar (resistant cases = 15, or 28.3%) and 78 unipolar (resistant cases = 20, or 25.6%) patients. Among the MDD patients, cluster "1" included the following components: "Psychic symptoms, depressed mood, suicide, guilty, insomnia" and "genitourinary, gastrointestinal, weight loss, insight". Altogether, with broadly defined "mixed features," this latter cluster correctly predicted treatment outcome in 80.8% cases of MDD. The same "broadly-defined" mixed features of depression (namely, the standard Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition-DSM-5-specifier plus increased energy, psychomotor activity, irritability) correctly classified 71.7% of BD cases, either as TRBD or not. LIMITATIONS: Small sample size and high rate of comorbidity. CONCLUSIONS: Although relying on different operational criteria and treatment history, TRD and TRBD seem to be consistently predicted by broadly defined mixed features among different clinical subtypes of depression, either unipolar or bipolar cases. If replicated by upcoming studies to encompass also biological and neuropsychological measures, the present study may aid in precision medicine and informed pharmacotherapy.

Efficacy, Safety, and Tolerability of Theta-Burst Stimulation in Mixed Depression: Design, Rationale, and Objectives of a Randomized, Double-Blinded, Sham-Controlled Trial.

INTRODUCTION: Mixed-specifier mood disorders are probably a different subgroup in terms of response to treatment, socio-demographic parameters, course, and family history. Here we describe the rationale and design of a clinical trial aimed to test the efficacy, safety, and tolerability of a non-pharmacological treatment known as theta-burst stimulation (TBS) for treating the mixed depressive episodes of both bipolar (I or II), and unipolar depression. METHODS: The study is designed as a randomized, sham-controlled, double-blinded clinical trial evaluating TBS for the treatment of moderate or severe major depressive episodes with mixed features of patients receiving at least one first or second-line pharmacological treatment for depressive episodes without adequate response. Ninety adult (18 to 65 years old) patients will be enrolled and submitted to 6-week (comprising 5 consecutive days a week sessions for the first 3 weeks and then 2 days a week for a further 3 week) of inhibitory followed by excitatory TBS in dorsolateral prefrontal cortex. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in Montgomery-Åsberg Depression Scale (MADRS) score over time and across groups. Cognitive parameters will also be assessed with neuropsychological tests. RESULTS: The clinical results will provide evidence about TBS as an adjunctive treatment for mixed depression treatment and neuropsychological parameters will contribute toward an improved understanding the effects of TBS in cognition. CONCLUSION: Our results could introduce a novel therapeutic technique for mixed depressive episodes of both bipolar and unipolar disorders. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT04123301; date of registration: 10/10/2019; URL: https://clinicaltrials.gov/ct2/show/NCT04123301?term=NCT04123301&rank=1.

The structure of mania: An overview of factorial analysis studies.

BACKGROUND: Operational definitions of mania are based on expert consensus rather than empirical data. The aim of this study is to identify the key domains of mania, as well as the relevance of the different signs and symptoms of this clinical construct. METHODS: A review of latent factor models studies in manic patients was performed. Before extraction, a harmonization of signs and symptoms of mania and depression was performed in order to reduce the variability between individual studies. RESULTS: We identified 12 studies fulfilling the inclusion criteria and comprising 3039 subjects. Hyperactivity was the clinical item that most likely appeared in the first factor, usually covariating with other core features of mania, such as increased speech, thought disorder, and elevated mood. Depressive-anxious features and irritability-aggressive behavior constituted two other salient dimensions of mania. Altered sleep was frequently an isolated factor, while psychosis appeared related to grandiosity, lack of insight and poor judgment. CONCLUSIONS: Our results confirm the multidimensional nature of mania. Hyperactivity, increased speech, and thought disorder appear as core features of the clinical construct. The mood experience could be heterogeneous, depending on the co-occurrence of euphoric (elevated mood) and dysphoric (irritability and depressive mood) emotions of varying intensity. Results are also discussed regarding their relationship with other constitutive elements of bipolar disorder, such as mixed and depressive states.

Mixed States: Historical Impact and Evolution of the Concept.

Mixed states have been discussed for more than 2 millennia. The theoretic conception of the coexistence of presumably opposite symptoms of mood or of different psychic domains is well established, although obscured by the presumed separation between bipolar and depressive disorders. Moreover, the lack of response to treatments and severe psychopathology raise important issues requiring urgent solution. The aim of this article was to review the development of the concept of mixed states from the classic literature to modern nosologic systems and to claim for the need of a new paradigm to address the still-open issues about mixed states.

The Neurobiology of Mixed States.

Interest in the coexistence of manic and depressive symptoms fostered hypotheses on neurobiological underpinnings of mixed states. Neurobiological properties of mixed states, however, have not been comprehensively described. The authors searched databases for articles on neurobiological markers related to mixed states. Results showed that mixed states are characterized by elevated central and peripheral monoamine levels, greater alterations in hypothalamic-pituitary-adrenal axis, increased inflammation, and greater circadian rhythms dysfunction than nonmixed forms. Furthermore, the magnitude of pathophysiologic alterations in mixed states exceeds those associated with nonmixed mania or depression and suggest that hyperactivation and hyperarousal are core features of mixed states.

Temporal Structure of Mixed States: Does Sensitization Link Life Course to Episodes?

Susceptibility to combined depressive and manic syndromes correlates strongly with arousal-related symptoms including impulsivity, anxiety and agitation. This relationship to a driven, "mixed" activation-depression state, generated by a life-long process, was described in classical times. Course of illness in mixed states includes increased episode frequency, duration, earlier onset, and association with addiction- and trauma/stress-related disorders. Mixed episodes have catecholamine and hypothalamic-pituitary-adrenocortical activity increased beyond nonmixed states of similar symptom severity. These properties resemble behavioral sensitization, where salient, survival-related stimuli (traumatic or rewarding) can generate persistently exaggerated responses with disrupted arousal and reward, with potential for suicide and other severe consequences.

The Role of Electroconvulsive Therapy in the Treatment of Severe Bipolar Mixed State.

Electroconvulsive therapy (ECT) results effective in two-thirds of the patients with severe and drug-resistant mixed states. The episode duration is the main predictor of nonresponse. This practice may increase the risk of mood destabilization and chronic complications and may decrease the chance of recovery in many patients. Compared with the burden of neurologic and metabolic side effects associated with long-term use of complex pharmacologic regimens, ECT should be considered a safe option with a very low incidence of severe adverse events and a long-term nondestabilizing effect.

Psychopathology of Mixed States.

Mixed states are frequent clinical pictures in psychiatric practice but are not well described in nosologic systems. Debate exists as to defining mixed states. We review factor and cluster analytical studies and prominent clinical/conceptual models of mixed states. While mania involves standard manic symptoms and depression involves standard depressive symptoms, core additional features of the mixed state are, primarily, psychomotor activation and, secondarily, dysphoria. Those features are more pronounced in mixed mania than in mixed depression but are present in both.

Diagnosis, Clinical Features, and Therapeutic Implications of Agitated Depression

Agitated "unipolar" depression is a clinical entity characterized by excitement together with depressed mood during the same episode. The clinical picture of agitated "unipolar" depression is characterized by a depressed and anxious mood with inner, psychic agitation, whereas motor agitation may or may not be present. Some investigators have conceptualized this disorder as a mixed affective state, laying on the bipolar disorder spectrum, but controversies still persist. The diagnosis of agitated "unipolar" depression has important prognostic and therapeutic implications, with many clinicians reporting difficulties to adequately diagnose and treat it.

The Ring of Fire: Childhood Trauma, Emotional Reactivity, and Mixed States in Mood Disorders.

Childhood trauma (CT) is strongly associated with bipolar disorder, possibly through emotional hyperreactivity (EH). Mixed symptoms/states (MSs) are associated with increased illness severity. The authors tested through a systematic review the association between CT and MSs. The authors systematically looked for studies exploring associations between MSs and CT, CT and EH, and EH and MSs. Most literature agrees that MSs are associated with CT; the latter was found to be associated to EH, which is in turn associated with MSs. The literature supports an association between CT and later development of MSs, possibly mediated through EH.

Mixed States in Early-Onset Bipolar Disorder.

Pediatric bipolar disorder (PBD) is a severe and chronic illness. The occurrence of mixed symptoms might add further risk of recurrence of treatment resistance and suicidality. Early recognition and treatment of mixed symptoms might prevent illness progression and development of suicide attempts. This article provides an update on the epidemiology, clinical profile, and treatment of youth with PBD with mixed states. Mixed states in PBD are characterized by higher rates of suicide and more chronic symptoms, and are associated with younger age of onset and greater comorbidity. A careful assessment for mixed states using standardized criteria is essential.