OBJECTIVES:Identifying factors predictive of long-term morbidity should improve clinical planning limiting disability and mortality associated with bipolar disorder (BD).METHODS:We analyzed factors associated with total, depressive and mania-related long-term morbidity and their ratio D/M, as %-time ill between a first-lifetime major affective episode and last follow-up of 207 BD subjects. Bivariate comparisons were followed by multivariable linear regression modeling.RESULTS:Total % of months ill during follow-up was greater in 96 BD-II (40.2%) than 111 BD-I subjects (28.4%; P=0.001). Time in depression averaged 26.1% in BD-II and 14.3% in BD-I, whereas mania-related morbidity was similar in both, averaging 13.9%. Their ratio D/M was 3.7-fold greater in BD-II than BD-I (5.74 vs. 1.96; P<0.0001). Predictive factors independently associated with total %-time ill were: [a] BD-II diagnosis, [b] longer prodrome from antecedents to first affective episode, and [c] any psychiatric comorbidity. Associated with %-time depressed were: [a] BD-II diagnosis, [b] any antecedent psychiatric syndrome, [c] psychiatric comorbidity, and [d] agitated/psychotic depressive first affective episode. Associated with %-time in mania-like illness were: [a] fewer years ill and [b] (hypo)manic first affective episode. The long-term D/M morbidity ratio was associated with: [a] anxious temperament, [b] depressive first episode, and [c] BD-II diagnosis.CONCLUSIONS:Long-term depressive greatly exceeded mania-like morbidity in BD patients. BD-II subjects spent 42% more time ill overall, with a 3.7-times greater D/M morbidity ratio, than BD-I. More time depressed was predicted by agitated/psychotic initial depressive episodes, psychiatric comorbidity, and BD-II diagnosis. Longer prodrome and any antecedent psychiatric syndrome were respectively associated with total and depressive morbidity.

OBJECTIVE:Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved.METHOD:We compared 2269 subjects with psychotic features in DSM-IV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs.RESULTS:In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses.CONCLUSION:SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders.

Background: Inferior response to lithium treatment has been reported in bipolar disorder (BD) patients with mania or hypomania following episodes of major depression (DMI) versus preceding depression (MDI), with intervening euthymic periods. However, additional characteristics of BD course-patterns require further assessment.Methods: We reviewed computerized clinical records and life-charts of 855 DSM-IV-TR BD-I or -II patients assessed and followed at mood-disorder centers in Cagliari or Rome to characterize their predominant course-sequences.Results: Morbidity over an average of 9.5 cycles in 18 years was characterized for sequencing of illness-episodes and euthymic intervals. Prevalent sequences included: major depression hypomania (15.0%), mania major depression (14.6%), major depression mania (11.6%), and rapid-cycling (9.6%). Among subjects grouped by course-sequences (based on mania, mixed-states, or hypomania and major or minor depression), depression-before-[hypo]mania (DMI)) cases were more likely to be women, diagnosed BD-II, have first-episodes of depressive or anxiety disorder, spend more time ill in depression, and benefit less with long-term mood-stabilizing treatments than with the opposite pattern (MDI) MDI patients were more likely to have substance abuse and receive long-term mood stabilizer treatments. Meta-analysis of 5 previous reports plus present findings found inferior treatment response in DMI vs. MDI cases at a pooled risk difference of 29% [CI: 18-40%1 (p < 0.0001).Limitations: Some data were retrospective and subject to recall bias, and treatment was clinical (non-randomized).Conclusions: The DMI course was strongly associated with first episode depression or anxiety, excess depressive morbidity, and inferior treatment response, especially for depression. (C) 2013 Elsevier B.V. All rights reserved

OBJECTIVE:To review the DSM-5 proposed criteria for mixed depression in light of robust and consistent historical and scientific evidence. METHOD:An extensive historical search, a systematic review of the papers used by DSM-5 as reference papers, and a PubMed search were performed. RESULTS:As Hippocrates, depressive mixed states have been described as conditions of intense psychic suffering, consisting of depressed mood, inner tension, restlessness, and aimless psychomotor agitation. In DSM-5, new criteria are proposed for a mixed features specifier, as part of depression either in major depressive disorder (MDD) or bipolar disorder. Those criteria require, as diagnostically specific, manic/hypomanic symptoms that are the least common kinds of symptoms that actually arise in depressive mixed states. The DSM-5 proposal is based, almost entirely, on a speculative wish to avoid 'overlapping' manic and depressive symptoms. Mixed states are, in fact, nothing but overlapping manic and depressive symptoms. CONCLUSION:In this article, we review the psychopathology and research on mixed depressive states, and try to demonstrate that the DSM-5 proposal has weak scientific basis and does not identify a large number of mixed depressive states. This may be harmful because of the different treatment required by these conditions.

Serra, G; Manfredi, G; Faedda, G; De Chiara, L; Sani, G; Koukopoulos, A; Koukopoulos, A; Girardi, P Author Information

ObjectivesThe aim of this paper is to present a brief update on temperament, emphasizing its overarching importance in the field of mood disorders and stressing its role as one of the cornerstones of the bipolar spectrum. The hypothesis, first proposed by Kraepelin, that temperament can predispose to or be a risk factor for or serve as a substrate for the development of manifest psychopathology, has been confirmed by numerous contemporary clinical studies. Classical and recent literature, in addition to empirical, systematic and experimental studies, demonstrate that affective temperaments can be considered as effective tools in identifying vulnerability to mood disorders. In recent years, therefore, attention to temperament and the relationship between temperamental traits and different psychopathological frames has become an increasingly common topic for study and research.MethodsTwo independent investigators carried-out literature search (D. Harnic and M. Mazza). The following databases were screened: PubMed, BioMedCentral, ISI Web of Science, and PsycINFO. The keywords used are: bipolar disorder; spectrum; temperament; subthreshold symptoms. Inclusion criteria include all publications from 1950 to 2010, with particular attention to reviews. Only the most significant and comprehensive contributions were included in this study. The objective of this work is not to conduct a systematic review of literature but to provide a concise but comprehensive overview of the link between temperament and the bipolar spectrum.ResultsIn contrast to the dichotomous conception proposed by Kraepelin that, until relatively recent times, considered mania and depression as two distinct and separate categories, Akiskal has posited a psychopathological "continuum" between temperament and affective disorders (bipolar spectrum). In fact, reconstructing the history of patients with mood disorders, and especially in those with bipolar disorder, temperamental traits can already be observed in the premorbid period and continue to persist in symptom-free intervals. Mood disorders should be considered as belonging to a continuum in which "pure" depression and "pure" mania represent the extremes of a spectrum defined by three main psychopathological dimensions: affectivity, thought and volitionlocomotion. The "pure" manic and depressive poles occur when the three axes move simultaneously in the same direction, the rest are mixed affective states, described in detail by Wilhelm Weygandt, a pupil of Kraepelin. In 1999, Akiskal and Pinto have proposed a schematic classification of the different forms of the bipolar spectrum, advancing the existence of seven distinct categorical subtypes (Table I). In DSM-V this schematization should have replaced the current system of classification of bipolar disorders, but it has not been accepted by the task force on mood disorders. Some of the most experienced researchers and psychiatrists have studied in depth the above stated issues and have devised various instruments (the most relevant of which are described) that can help the clinician, in everyday practice, to identify even the most blurred dimensions of affective disorders. Tests, currently used both in the field of research and in the clinical field, were thus conceived in order to capture, in as much detail as possible, the protean expressions of the patients' symptoms.ConclusionsAffective disorders extend their dimensions beyond the expression of euphoria or depression alone, and appear to include, among others, conditions like anxiety, panic, irritability and emotional instability. In interpreting and diagnosing the varied expression of the bipolar spectrum, psychiatrists are today facing a major challenge in daily clinical practice. One of the main factors complicating this task is temperamental instability which often is the background of the attenuated bipolar spectrum. In recent years, attention to temperament and the relationship between temperamental traits and different psychopathological frames has become an increasingly frequent topic for study and research. Temperamental "dysregulation" is the pathological foundation of mood disorders and its alteration, in individuals, reflects a marked predisposition to develop a mood disorder. The need to clarify some aspects of this complex situation regarding temperament and subthreshold manifestations has disclosed the need to create new assessment tools that allow a refinement of the diagnostic process and, consequently, an individualization of psychopharmacotherapy.

Objectives Temperament represents one of the basic elements of bipolar spectrum. Methods A systematic search was undertaken in MEDLINE (from 1977 to 2007) to obtain articles published in English regarding the association of temperament and bipolar disorder. Keywords used were “temperament”, “bipolar disorder”, “assessment”, “bipolar spectrum”, “subthreshold”. Results In opposition to the dichotomic conception which up to the end of XIX century considered mania and depression as two distinct and separate categories, Kraepelin has postulated a psychopathological “continuum” between temperament and affective disorders called “bipolar spectrum”. This concept has been reintroduced in contemporary psychiatry by Akiskal's works. By rebuilding the history of patients affected by bipolar disorder, temperamental traits can be already observed in the pre-morbid period and can also persist during disorder-free intervals. Conclusions By interpreting and diagnosing multiple expressions of bipolar spectrum, psychiatrists today are facing one of the most important challenges in everyday clinical practice. The temperamental “dysregulation” is the pathological basis of mood disorders and some temperamental traits in individuals can reflect a predisposition to develop a mood disorder.

Treatment of mixed/agitated depression and psychotic depression with antidepressants may increase agitation, insomnia and suicidal ideation and impulses. We propose that mixed depression is a syndrome produced by high nervous energy within the depressive syndrome, and that it is not having common features with mania. According to our proposed criteria, 346 out of 1037 (33%; 38% for women and 25% for men) patients with Major Depression examined at our Centre suffered from mixed depression, almost half of them with motor agitation. In 56% of cases the depressive mixed episode had started in association with antidepressant treatments. The basic rule for the treatment of these patients is to suspend antidepressants if they are being administered or not to administer them until mixed symptoms and agitation have subsided; treatment with neuroleptics, benzodiazepenes, anticonvulsants, lithium or ECT is proposed.

Melancholia has the greatest tradition in psychiatry and agitated melancholia has always been considered the most severe form of affective states. Descriptions of agitated melancholia are found in the ancient writers Hippocrates and Aretaeus, nosologists of the eighteenth and nineteenth centuries, like Boissier de Sauvages, William Cullen, JCA Heinroth and Wilhelm Griesinger, to Kraepelin who describes among mixed states the excited depression. The first to use the term "melancholia agitans" was Franz Richarz, published in 1858. More commonly termed as melancholia agitata, it was widely employed in the second half of the nineteenth century, and it later became agitated depression. Today melancholia is relegated as a specifier of major depression in the DSM system and agitated melancholia has disappeared. We believe that the reinstitution for melancholia and agitated melancholia as independent diagnoses could lead to a better outcome for melancholic patients and it would avoid the therapeutic hazards of the agitated forms when treated as major depressions

Objectives To review the available preclinical and clinical evidence suggesting a possible role of endocannabinoid system in the neurobiology of mood disorders.Methods Critically review the most recent data of the literature and of the authors publications on the role of endocannabinoid system in the neurobiology of mood disorders.Results The term "endocannabinoid system"refers to the recently discovered neuromodulator system comprising cannabinoid receptors (which bind tetrahydrocannabinol (THC), the major active component of cannabis) and their endogenous ligands. At least two types of cannabinoid receptors have been identified, CB1 and CB2 receptors. The CB1 receptor is widely distributed in neuronal terminals, while the CB2 receptor is extensively expressed throughout the immune system, but are present also in the brain. The main endogenous ligands (endocannabinoids) of cannabinoid receptors are anandamide and 2AG (2 arachidonoylglycerol). Following the release of endocannabinoids, these compounds exert an action on cannabinoid receptors and are rapidly inactivated by uptake and degradation. The degradation of endocannabinoids is achieved by means of two specific enzymes, the fatty acid amide hydrolase (FAAH) and the monoacylglyceride lipase (MAGL) enzymes. FAAH degrades anandamide, whereas the MAGL degrades 2 AG. This article, after a brief description of the clinical picture of mood disorders and after detailing the current hypotheses on the pathophysiology of depression and mania, critically reviews the available preclinical and clinical evidence suggesting a possible role of the endocannabinoid system in the neurobiology of mood disorders. Many animal studies suggest that the direct or indirect (i.e., endocannabinoid reuptake inhibition or reduced enzymatic degradation) stimulation of cannabinoid CB1 receptors exerts an antidepressant like action. On the other hand, several animal models of depression seem to be associated to a decreased activity of the endocannabinoid system. On the contrary, we have recently demonstrated that the supposed antidepressantlike activity of the CB1 receptor antagonist, Rimonabant, is a "false positive"effect, thus providing an experimental support to explain the obvious contradiction of a drug claimed to be antidepressant in animals, but withdrawn from the market after few years of clinical use due to its depression inducing potential.Conclusions The hypothesis that the stimulation of cannabinoid CB1 receptors may result in an antidepressant effect is consistent with the clinical experience with cannabis use in humans. Thus, the direct agonists of CB1 receptors, as well as endocannabinoid reuptake and degradation inhibitors should be considered as potential antidepressant drugs. These observations led us to speculate that these compounds could share with classical antidepressants not only the therapeutic effect but also the ability to induce mania/hypomania and worsen the course of manic depressive disorders. In fact, as it has been suggested for classical antidepressants, cannabis use, even more than classical antidepressants, appear to be associated with early onset of bipolar disorders, worsening of its course and impaired mood stabilization. Therefore, we suggest that the use of cannabinoid CB1 receptor agonists should be used with caution in the treatment of depression, and preferably in treatment resistant patients.

Background Gender is known to modulate the clinical course and severity of bipolar disorder (BD). Although cognitive abnormalities are an established feature of BD, there is limited information regarding whether gender also influences the pattern and severity of cognitive impairment. Method We evaluated the performance of 86 remitted patients with BD, type 1, (BD-I) (36 male and 50 female) and 46 healthy participants (21 male and 25 female) on tasks of general intellectual ability, memory encoding, recognition and retrieval, response inhibition and executive function (abstraction and perseveration). The impact of illness severity in patients was assessed using the global assessment of functioning (GAF). Results We found a gender effect and an interaction between diagnosis and gender on immediate memory, implicating encoding and retrieval processes, both showing male BD-I patients being disadvantaged compared with female patients and healthy controls. Immediate memory correlated with GAF scores and this association was statistically significant for male BD-I patients. Conclusions Our findings suggest that gender differences in BD-I are associated with memory function, particularly processes relating to encoding and retrieval, and may contribute to poor functional outcome particularly in men.

ObjectiveThe goal of this paper is to examine the triggering factors associated with the emergence of manic episodes and see whether the cyclicity of BPI patients is driven exclusively by endogenous factors or it is determined also by exogenous triggering factors. After a historical overview of the evolution of the concept of cyclicity and its fundamental significance in manicdepressive illness, we look at the intimate relationship between mania and depression and we discuss the hypothesis of the primacy of mania.MethodsWe reviewed the clinical charts of 100 consecutive index manias that were examined at the Centro Lucio Bini in Rome. The diagnosis was based on the DSM-IV diagnostic criteria for manic episode. We focus the search on the presence of factors recognized in literature as able to trigger a mania . We also examined the premorbid temperament of these patients applying Akiskal and Mallya's criteria.ResultsWe found that 80 manias occurred in association with one or more triggering factors and only in 20 manias we did not find any evident triggering factor. Thirty manias were trigged by antidepressant treatments, 18 by drug abuse, 17 by withdrawal of antimanic treatments, 4 by very distressing life events, 3 by cortisone treatment, 3 by sleep deprivation, 2 by child-birth, one by jet-lag, one by excessive thyroxine dose, and one by cranial injury. As far as the temperament of these patients is concerned we found that 69 were hyperthymic, 12 cyclothymic, 8 dysthymic, and 4 irritable.ConclusionsExternal factors may act on a particulary excitable temperament and trigger a manic episode. Temperament is an endogenous factor, but exogenous factors may determine the cyclic course of BPI disorder.We finally present a possible neurobiological explanation supporting the view that treatment with antidepressant drugs, by increasing dopaminergic transmission in the mesolimbic system, may trigger acute mania and destabilise long-term course.

OBJECTIVE:The diagnostic entity of major depressive episode includes both simple and agitated or mixed depression. Mixed depression is characterized by a full depressive episode with several symptoms of excitatory nature. Mixed depressions worsen if treated with antidepressants.METHOD:We have reviewed the clinical charts of the 2141 patients treated at the Centro Lucio Bini of Rome from January 1999 to June 2006. These patients were diagnosed according to DSM-IV criteria. Research diagnostic criteria were applied for agitated depression with motor agitation and Author's diagnostic criteria for agitated depression without motor agitation.RESULTS:One thousand and twenty-six patients had a depressive episode as index episode. Three hundred and forty six (33%) were mixed depressive states. One hundred and thirty eight (44%) of them were spontaneous; in 173 cases, the onset of the mixed depression was associated with antidepressants.CONCLUSION:Psychic and motor agitation are considered equally important for the definition of agitated depression. Treating agitated depression with antidepressants worsens the clinical picture. The use of Electroconvulsive Therapy (ECT), neuroleptics and anticonvulsants are recommended. The term Melancholia Agitata is proposed for agitated (mixed) depression.

An original method based on the use of high-performance liquid chromatography with both coulometric and diode array detection has been developed for the therapeutic drug monitoring of patients with bipolar disorders being treated with olanzapine and lamotrigine. Chromatographic separation was achieved on a reversed-phase C8 column (150 × 4.6 mm internal diameter, 5 μm) using a mobile phase composed of methanol (27%) and a 50.0 mmol/L, pH 3.5 phosphate buffer (73%). For the analysis of olanzapine and its main metabolite, N-desmethylolanzapine, a coulometric detector was used, with electrode 1 set at -200 mV and electrode 2 at +500 mV. Lamotrigine was determined using a diode array detection at 220 nm. The two detectors were connected in series. For the analysis of biological samples, a clean-up procedure was implemented by means of solid-phase extraction using phenyl cartridges and eluting the analytes with methanol; only a small volume of plasma (150 μL) was needed to analyze both olanzapine and lamotrigine. Linear responses were obtained between 0.1 and 50.0 ng mL−1 for olanzapine, 0.1 and 25.0 ng mL−1 for N-desmethylolanzapine, and between 0.25 and 10.0 μg mL−1 for lamotrigine. The extraction yield values were always higher than 90% for all the analytes, with precision (expressed as relative standard deviation values) lower than 3.4%. The method was applied successfully to some human plasma samples drawn from bipolar patients undergoing combined therapy with the two drugs. Satisfactory values for accuracy were obtained, with mean recovery higher than 91%. Thus, the method appears suitable for the investigation of the chemical-clinical correlations in patients receiving therapy with olanzapine and lamotrigine.

BackgroundMany guidelines describe the theory and practice of electroconvulsive therapy (ECT). From a scientific and clinical point of view, ECT is an effective treatment for severe depressive episodes and depressive syndromes resistant to other treatments. Furthermore, ECT has been proven useful in schizophrenic, schizoaffective disorders and in manic episodes resistant to other treatments. ECT has an important indication in malignant catatonia. It causes transient adverse effects. Of special importance for the patient are memory disturbances which sometimes persist after the end of the treatment.ResultsThe new methods of administering the electric stimulus, its continuous adaptation during the treatment cycle and the discontinuation of medications that potentially might interfere with cognitive processes reduce the intensity and frequency of memory loss. In any case, they are always reversible. ECT has a high safety profile and does not cause structural brain damage, according to the most recent studies. There are no absolute contraindications to ECT.ConclusionThe risk of mortality is linked to risks inherent in anaesthesia and it is, however, very low, i.e., 1: 30,000. The combined administration of ECT and psychotropic drugs is considered essentially safe. ECT comprises various specific and selective mechanisms of action. Specific neurobiological and neurochemical changes take place in precise brain areas, induced by the epileptic seizure and conditioned by the wave shape of the electrical stimulus, the charge used, the position of the electrodes and the number of treatments.