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Increasing evidence highlights bipolar disorder as being associated with impaired neurogenesis, cellular plasticity, and resiliency, as well as with cell atrophy or loss in specific brain regions. This has led most recent research to focus on the possible neuroprotective effects of medications, and particularly interesting findings have emerged for lithium. A growing body of evidence from preclinical in vitro and in vivo studies has in fact documented its neuroprotective effects from different insults acting on cellular signaling pathways, both preventing apoptosis and increasing neurotrophins and cell-survival molecules. Furthermore, positive effects of lithium on neurogenesis, brain remodeling, angiogenesis, mesenchymal stem cells functioning, and inflammation have been revealed, with a key role played through the inhibition of the glycogen synthase kinase-3, a serine/threonine kinase implicated in the pathogenesis of many neuropsychiatric disorders. These recent evidences suggest the potential utility of lithium in the treatment of neurodegenerative diseases, neurodevelopmental disorders, and hypoxic-ischemic/traumatic brain injury, with positive results at even lower lithium doses than those traditionally considered to be antimanic. The aim of this review is to briefly summarize the potential benefits of lithium salts on neuroprotection and neuroregeneration, emphasizing preclinical and clinical evidence suggesting new therapeutic potentials of this drug beyond its mood stabilizing properties.

BackgroundDiagnostic criteria are not always useful to discriminate major depression with anxious distress (ADS-D; Diagnostic and Statistical Manual for Mental Disorders, version-5 [DSM-5] criteria) from mixed depression (Koukopoulos’ criteria; KMX-D). So, clinicians need alternative tools to improve their diagnostic ability and to choose the most appropriate treatment. The aim of the present study is to identify socio-demographic and clinical features that discriminate patients with ADS-D from those with KMX-D.MethodsTwo hundred and forty-one consecutive outpatients with unipolar (51%) and bipolar (49%) disorder, fulfilling DSM-5 criteria for a current major depressive episode (MDE) and with a 21-item Hamilton Depression Rating Scale score ≥ 14, were recruited and treated in a prospective observational study.ResultsTen percent of patients met criteria for KMX-D, 22% ADS-D, and 37% for both. Irritable premorbid temperament, mixed depression polarity at onset, mixed depression recurrence, and a high number of mania symptoms at intake were typical features of patients with KMX-D. Depressive polarity at onset, a low number of mania symptoms at intake, and generalized anxiety disorder comorbidity were typical features of patients with ADS-D. Multinomial logistic regression confirmed that higher rate of irritable temperament and higher Young Mania Rating Scale total score differentiated patients with KMX-D from patients with pure MDE.ConclusionOur findings suggest some clinical features that could help differentiate between ADS-D and KMX-D in patients meeting both conditions and to select the appropriate treatment. However, the small sample size may have limited the power to detect differences between the groups. Further research is needed to confirm the results of present study.

This study seeks to offer a contribution to the method of subtyping major depressed patients by exploring the possible relationships between circulating brain-derived neurotrophic factor (BDNF), different peripheral inflammatory/metabolic markers in the blood and clinical characteristics. Thirty-nine patients, thoroughly diagnosed according to the DSM-5 criteria, underwent a comprehensive set of evaluations encompassing structured interviews, rating scales and a panel of blood tests. Correlation and comparison analyses were carried out by means of non-parametric statistical tests. Concurrently, a principal component analysis was performed to explain biochemical variance. The findings of our research unveiled that leukocyte counts, their ratios and other inflammatory parameters are positively correlated with depression scores. Moreover, we found variations within the BDNF pools of depressed patients. Specifically, higher levels of platelet-poor plasma BDNF (PPP-BDNF) were correlated with augmented inflammatory markers in patients showing specific episode characteristics, whereas reduced platelet BDNF (PLT-BDNF) provided a better indication of the changes that were linked to a diagnosis of long-term depression. Our findings suggest that PPP-BDNF and PLT-BDNF might differentiate depression conditions. They also imply usefulness in appraising peripheral biomarker profiles in patients for a deeper characterization of major depressive episodes. At the same time, it is plausible that they might constitute novel avenues for developing more tailored therapeutic strategies for patients with MDs.

Epidemiological, clinical, and treatment response characteristics of major depression with anxious distress (ADS) are quite similar to those of mixed depression, but no study investigated the symptom interplay of these conditions. To analyze the correlations among symptom criteria for major depression with ADS and for mixed depression using a network analysis. Two hundred and forty-one outpatients with major depression were consecutively recruited. DSM-5 criteria for major depression with ADS or with mixed features (MF) and Koukopoulos' criteria for mixed depression (MXD) were assessed using a structured clinical interview. A total of 58.9% of patients met DSM-5 criteria for major depression with ADS, 48.5% for MXD, and 2.5% for major depression with MF, so that the symptoms of this specifier were excluded from the network analysis. The most frequent symptoms were difficulty concentrating due to worries (57.7%), feeling keyed up or on edge (51%) (major depression with ADS), and psychic agitation or inner tension (51%) (MXD). Psychic agitation or inner tension had a central position in the network and bridged MXD to major depression with ADS through feeling keyed up or on edge. Criteria for major depression with ADS and for MXD are partially overlapping, with psychic agitation or inner tension and feeling keyed up or on edge that feature in both conditions and are difficult to distinguish in clinical practice. The clarification of the relationship between these two psychopathological conditions could bring important implications for diagnosis, prognosis, and treatment of depressive episodes.

Several studies investigating bipolar disorders have shown that polarity of onset can predict differences in symptomatology, course, and prognosis. Frequently, however, research on the topic has examined only bipolar I inpatients and has not included patients with mixed onset. The aim of the present naturalistic study was to evaluate the clinical characteristics and illness course of a consecutive sample (407 outpatients, 58.7% with bipolar I (BD-I) and 41.3% with bipolar II (BD-II) disorder) according to polarity of onset: depressive (DP-o); manic/hypomanic (HM-o); or mixed – broadly defined to include agitated depression for BD-II – onset (MX-o). As compared with patients in the other two groups: a) DP-o patients (67.3%) were more frequently affected by BD-II and had lower ratings for psychotic symptoms; b) HM-o patients (17%) had a higher rate of family history for psychosis and a lower rate of suicide attempts; and c) patients in the MX-o group (15.7%) more frequently showed substance abuse and had a higher number of mixed recurrences per year. In the BD-II group, MX-o patients more frequently attempted suicide. The present study's main limitations are those of retrospective assessment of onset polarity and lack of treatment-impact evaluations over illness course. In conclusion, we confirm clinical expression differences in bipolar disorder in function of polarity of onset and underscore the importance of carefully considering broadly defined mixed state when examining polarity of onset. Further investigations are required to confirm the present study's results.

To identify demographic and clinical characteristics of bipolar depressed patients who require antidepressant (AD) augmentation, and to evaluate the short- and long-term effectiveness and safety of this therapeutic strategy. One hundred twenty-two bipolar depressed patients were consecutively recruited, 71.7% of them received mood stabilizers (MS)/second-generation antipsychotics (SGA) with AD-augmentation and 28.3% did not. Patients were evaluated at baseline, and after 12 weeks and 15 months of treatment. The AD-augmentation was significantly higher in patients with bipolar II compared with bipolar I diagnosis. Patients with MS/SGA + AD had often a seasonal pattern, depressive polarity onset, depressive index episode with anxious features, a low number of previous psychotic and (hypo)manic episodes and of switch. They had a low irritable premorbid temperament, a low risk of suicide attempts, and a low number of manic symptoms at baseline. After 12 weeks of treatment, 82% of patients receiving ADs improved, 58% responded and 51% remitted, 3.8% had suicidal thoughts or projects, 6.1% had (hypo)manic switch, and 4.1% needed hospitalization. During the following 12 months, 92% of them remitted from index episode, 25.5% did not relapse, and 11% needed hospitalization. Although at the start advantaged, patients with AD-augmentation, compared with those without AD-augmentation, did not significantly differ on any outcome as well on adverse events in the short- and long-term treatment. Our findings indicate that ADs, combined with MS and/or SGA, are short and long term effective and safe in a specific subgroup for bipolar depressed patients.

Depressive symptoms and episodes dominate the long-term course of bipolar disorder and are associated with high levels of disability and an increased risk of suicide. However, the treatment of bipolar depression has been poorly investigated in comparison with that of manic episodes and unipolar major depressive disorder. The goal of treatment in bipolar depression is not only to achieve full remission of acute symptoms, but also to avoid long-term mood destabilization and to prevent relapses. A depressive presentation of bipolar disorder may often delay the appropriate management and, thus, worsen the long-term outcome. In these cases, an accurate screening for diagnostic indicators of a possible bipolar course of the illness should guide the therapeutic choices, and lead to prognostic improvement. Antidepressant use is still the most controversial issue in the treatment of bipolar depression. Despite inconclusive evidence of efficacy and tolerability, this class of agents is commonly prescribed in acute and long-term treatment, often in combination with mood stabilizers. In this article, we review available treatment options for bipolar depression, and we shall provide some suggestions for the management of the different presentations of depression in the course of bipolar disorder.

Despite the great quantity of evidence supporting the efficacy of lithium in the maintenance treatment of bipolar disorder (BD), its use has often been limited because of issues about the management of this compound. W aimed to evaluate the use of lithium in common clinical practice and to identify possible relationships between the trend over time of serum lithium levels and clinical course of the illness. 98 patients with bipolar I and bipolar II disorder (DSM-IV-TR) on maintenance treatment with lithium salts were recruited and followed up in a naturalistic trial at the Day Hospital of Psychiatric Clinic of Pisa. Diagnosis was confirmed using a structured interview, the SCID-I. During symptom assessment, the Clinical Global Impression-Bipolar Version Scale (CGI-BP) was used. The sample is made up mainly of BI patients (87.8%) and lithium is used in association with anticonvulsants in 63%. Less than half of the sample (48%) presents average serum lithium levels in the therapeutic range (0.5-0.8 mEq/L); serum values of lithium within the range were seen more frequently in patients with manic/mixed episode, with manic/mixed polarity of onset, with a greater number of previous episodes, with a higher percentage of rapid cycling and in subjects treated with lithium associated with anticonvulsants. During the follow-up patients with average serum lithium levels within the therapeutic range obtained a clinical improvement in a significantly greater proportion compared to patients with average serum lithium levels lower than 0.50 mEq/L. In clinical practice, lithium is often used at doses determining serum levels at the lower limits of the therapeutic range. Preliminary data on the prospective course of the illness support the importance of maintaining serum values of lithium within the therapeutic range.

Despite the great quantity of evidence supporting the efficacy of lithium in the maintenance treatment of bipolar disorder (BD), its use has often been limited because of issues about the management of this compound. We aimed to evaluate the use of lithium in common clinical practice and to identify possible relationships between the trend over time of serum lithium levels and clinical course of the illness. Methods. 98 patients with bipolar I and bipolar II disorder (DSM-IV-TR) on maintenance treatment with lithium salts were recruited and followed up in a naturalistic trial at the Day Hospital of Psychiatric Clinic of Pisa. Diagnosis was confirmed using a structured interview, the SCID-I. During symptom assessment, the Clinical Global Impression-Bipolar Version Scale (CGI-BP) was used. Results. The sample is made up mainly of BI patients (87.8%) and lithium is used in association with anticonvulsants in 63%. Less than half of the sample (48%) presents average serum lithium levels in the therapeutic range (0.5-0.8 mEq/L); serum values of lithium within the range were seen more frequently in patients with manic/mixed episode, with manic/mixed polarity of onset, with a greater number of previous episodes, with a higher percentage of rapid cycling and in subjects treated with lithium associated with anticonvulsants. During the follow-up patients with average serum lithium levels within the therapeutic range obtained a clinical improvement in a significantly greater proportion compared to patients with average serum lithium levels lower than 0.50 mEq/L. Discussion. In clinical practice, lithium is often used at doses determining serum levels at the lower limits of the therapeutic range. Preliminary data on the prospective course of the illness support the importance of maintaining serum values of lithium within the therapeutic range.

BackgroundMania with chronic course has been overlooked in the recent literature. Our aim was clinically to characterise and validate this form of mania.MethodWe evaluated 155 people with DSM–III–R mania and assessed their family history, temperament, symptomatology and course. We used a semi-structured interview for mood disorders, as well as the Comprehensive Psychopathological Rating Scale and the Scale for the Assessment of Positive Symptoms.ResultsTwenty (13%) had a chronic course arising from a background of hyperthymic temperament and recurrent mania, with a deteriorative pattern. Clinically, they were characterised by a significantly high rate of almost constant euphoria, grandiose delusions and related delusions, but had relatively low rates of sleep disturbance, psychomotor agitation and hypersexuality.ConclusionEven with current therapies a significant number of people with bipolar disorders have a deteriorative outcome associated with the gradual disappearance of acute mania with an increase in mregalomanic delusions, alienation from loved ones and decreased likelihood of medical and psychiatric care.