Biological correlates of treatment resistant depression: a review of peripheral biomarkers.

Introduction: Many patients fail to respond to multiple antidepressant interventions, being defined as "treatment-resistant depression" (TRD) patients. TRD is usually associated with increased severity and chronicity of symptoms, increased risk of comorbidity, and higher suicide rates, which make the clinical management challenging. Efforts to distinguish between TRD patients and those who will respond to treatment have been unfruitful so far. Several studies have tried to identify the biological, psychopathological, and psychosocial correlates of depression, with particular attention to the inflammatory system. In this paper we aim to review available studies assessing the full range of biomarkers in TRD patients in order to reshape TRD definition and improve its diagnosis, treatment, and prognosis. Methods: We searched the most relevant medical databases and included studies reporting original data on possible biomarkers of TRD. The keywords "treatment resistant depression" or "TRD" matched with "biomarker," "inflammation," "hormone," "cytokine" or "biological marker" were entered in PubMed, ISI Web of Knowledge and SCOPUS databases. Articles were included if they included a comparison with healthy controls (HC). Results: Of the 1878 papers identified, 35 were included in the present study. Higher plasma levels of IL-6 and TNF-α were detected in TRD patients compared to HC. While only a few studies on cortisol have been found, four papers showed elevated levels of C-reactive protein among these patients and four articles focused on immunological cells. Altered kynurenine metabolism in TRD patients was reported in two studies, while contrasting results were found with regard to BDNF. Conclusion: Only a few biological alterations correlate with TRD. TNF-α seems to be the most relevant biomarker to discriminate TRD patients from both HC and treatment-responsive MDD patients. Moreover, several discrepancies among studies have been found, due to methodological differences and the lack of a standardized diagnostic definition of TRD.

A Systematic Review on the Effectiveness of Antipsychotic Drugs on the Quality of Life of Patients with Schizophrenia.

Pharmacological antipsychotic drug interventions represent the cornerstone of the management of patients with schizophrenia and other psychotic spectrum disorders. The choice of the "best" treatment should be made on the basis of several clinical domains. However, despite available treatments, the quality of life reported by patients with schizophrenia taking antipsychotics is still very poor, and this outcome is rarely taken into account in trials assessing the efficacy and effectiveness of antipsychotic treatments. Therefore, we performed a systematic review in order to assess the impact of antipsychotic treatment on patients' quality of life. In particular, we aimed to identify any differences in the improvement in quality of life according to the (a) type of formulation of antipsychotic drugs (i.e., oral vs. depot vs. long-acting injectable); (b) type of the drug (first vs. second vs. third generation); and (c) patients' clinical characteristics. One hundred and eleven papers were included in the review. The main findings were as follows: (1) quality of life is usually considered a secondary outcome in trials on the efficacy and effectiveness of drugs; (2) second-generation antipsychotics have a more positive effect on quality of life; and (3) long-acting injectable antipsychotics are associated with a more stable improvement in quality of life and with a good safety and tolerability profile. Our systematic review confirms that quality of life represents a central element for selecting the appropriate treatment for people with schizophrenia. In particular, the availability of new treatments with a better tolerability profile, a proven effectiveness on patients' cognitive and social functioning, and with a more stable blood concentration might represent the appropriate strategy for improving the quality of life of people with schizophrenia.

Effect of affective temperament on illness characteristics of subjects with bipolar disorder and major depressive disorder.

BACKGROUND: Affective temperaments represent the stable, biologically determined substrates of mood disorders. The relationship between affective temperaments and bipolar disorder (BD) or major depressive disorder (MDD) has been described. However, the strength of such relationship should be tested while considering other factors influencing the diagnosis of BD/MDD. Literature also lacks a comprehensive description of the interplay between affective temperament and characteristics of mood disorders. The aim of the present study is to address these issues. METHODS: This is a multicentric observational study including 7 Italian university sites. Five-hundred-fifty-five euthymic subjects with BD/MDD were enrolled and further divided in those with hyperthymic (Hyper, N = 143), cyclothymic (Cyclo, N = 133), irritable (Irr, N = 49), dysthymic (Dysth, N = 155), and anxious (Anx N = 76) temperaments. Linear, binary, ordinal and logistic regressions were performed to assess the association between affective temperaments and i) diagnosis of BD/MDD; ii) characteristics of illness severity and course. RESULTS: Hyper, Cyclo and Irr were more likely to be associated with BD, together with earlier age of onset and presence of a first-degree relative with BD. Anx and Dysth were more associated with MDD. Differences in association between affective temperaments and characteristics of BD/MDD were observed for hospital admissions, phase-related psychotic symptoms, length and type of depression, comorbidity and pharmacological intake. LIMITATIONS: Small sample size, cross-sectional design, recall biases. CONCLUSION: Specific affective temperaments were associated to certain characteristics of illness severity and course of BD or MDD. Evaluation of affective temperaments might help a deeper understanding of mood disorders.

Does the Brain Matter? Cortical Alterations in Pediatric Bipolar Disorder: A Critical Review of Structural and Functional Magnetic Resonance Studies.

Pediatric bipolar disorder (PBD) is associated with significant psychosocial impairment, high use of mental health services and a high number of relapses and hospitalization. Neuroimaging techniques provide the opportunity to study the neurodevelopmental processes underlying PBD, helping to identify the endophenotypic markers of illness and early biological markers of PBD. The aim of the study is to review available studies assessing structural and functional brain correlates associated with PBD. PubMed, ISI Web of Knowledge and PsychINFO databases have been searched. Studies were included if they enrolled patients aged 0-18 years with a main diagnosis of PBD according to ICD or DSM made by a mental health professional, adopted structural and/or functional magnetic resonance as the main neuroimaging method, were written in English and included a comparison with healthy subjects. Of the 400 identified articles, 46 papers were included. Patients with PBD present functional and anatomic alterations in structures normally affecting regulations and cognition. Structural neuroimaging revealed a significant reduction in gray matter, with cortical thinning in bilateral frontal, parietal and occipital cortices. Functional neuroimaging studies reported a reduced engagement of the frontolimbic and hyperactivation of the frontostriatal circuitry. Available studies on brain connectivity in PBD patients potentially indicate less efficient connections between regions involved in cognitive and emotional functions. A greater functional definition of alteration in brain functioning of PBD patients will be useful to set up a developmentally sensitive targeted pharmacological and nonpharmacological intervention.

What influences psychological functioning in patients with mood disorders? The role of clinical, sociodemographic, and temperamental characteristics in a naturalistic study.

BACKGROUND: The present study aims to assess clinical and psychological correlates of psychological functioning in patients with mood disorders, in a naturalistic setting. In particular, we aimed to describe which sociodemographic, clinical, and temperamental dispositions are more frequently associated with poor psychological functioning, and to describe the association between cognitive and psychological functioning in euthymic patients with major depression and bipolar disorder. METHODS: Inclusion criteria were as follows: (1) diagnosis of major depression, or bipolar disorder type I or II; (2) age between 18 and 65 years; and (3) being in a stable phase of the disorder. Patients' psychiatric symptoms, quality of life, affective temperaments, and impulsivity were investigated with validated assessment instruments. RESULTS: 166 patients have been recruited, mainly female (55.4%), whose mean age was 47.1 ± 14.2 years. 42.6% of individuals reported a diagnosis of major depression. According to regression analyses, poor cognitive performance (p < 0.05), reduced perceived quality of life (p < .0001), lifetime suicide attempts (p < 0.01), and increased trait-related impulsivity (p <0 .001) strongly correlated with poor psychological functioning. Moreover, cyclothymic and irritable dispositions were also associated with poor social functioning (p < 0.01), whereas hyperthymic affective disposition was associated to a better psychological performance (p < 0.01). CONCLUSIONS: Our results support the evidence that patients with mood disorders should be assessed for psychological functioning and affective dispositions, to identify patients at higher risk to develop worse long-term outcomes and to develop targeted interventions.

Physical comorbidities in patients with severe mental disorders: a brief narrative review on current challenges and practical implications for professionals.

A paradox of the modern world is represented by the increasing rate of comorbidities, although the life expectancy is increasing worldwide, the number of disease-free years is not improving consequently. Physical comorbidities are often overlooked in people with severe mental disorders, although this problem needs to be adequately managed since it is associated with a worse quality of life and a poorer personal and social functioning. In this paper, we aim to: 1) carry out a narrative review of the recent literature in order to provide an update on the prevalence and incidence of the most frequent comorbid physical disorders in people with severe mental disorders; 2) highlight the most important difficulties in managing comorbidities in people with severe mental disorders in ordinary clinical care; 3) discuss possible solutions to overcome those difficulties, particularly through the role of education and scientific associations.

Trait-Related Impulsivity, Affective Temperaments and Mood Disorders: Results from a Real-World Multicentric Study.

Trait-related impulsiveness is highly prevalent in patients with mood disorders, being associated with negative outcomes. The predictive role of affective temperaments on trait-related impulsivity is still understudied. The aim of the present study is to investigate the relationship between impulsivity and affective temperaments in a sample of euthymic patients with mood disorders. This is a real-world multicentric observational study, carried out at the outpatient units of seven university sites in Italy. All patients filled in the short version of Munster Temperament Evaluation of the Memphis, Pisa, Paris and San Diego and the Barratt Impulsiveness Scale. The study sample included 653 participants, mainly female (58.2%), with a mean age of 46.9 (±14.1). Regression analyses showed that higher levels of trait-related impulsivity were associated to suicide attempts (p < 0.000), the presence of psychotic symptoms during acute phases (p < 0.05), a seasonal pattern (p < 0.05), a lower age at onset of the disorder (p < 0.05), cyclothymic (p < 0.01) and irritable temperaments (p < 0.01). The results of our study highlight the importance to screen patients with mood disorders for impulsivity and affective temperaments in order to identify patients who are more likely to present a worse outcome and to develop personalized and integrated early pharmacological and psychosocial treatment plans. Novelties of the present paper include the recruitment of patients in a stable phase, which reduced possible bias in patients' self-reports, and the multicentric nature of the study, resulting in the recruitment of a large sample of patients with mood disorders, geographically distributed across Italy, thus improving the generalizability of study results.

Vitamin D Deficiency and Risk Factors Related to Acute Psychiatric Relapses in Patients with Severe Mental Disorders: A Preliminary Study.

Previous studies have indicated that vitamin (Vit) D deficiency is frequent in psychiatric patients, regardless of diagnostic category. We aimed to assess whether acute psychiatric relapses in inpatients was associated with Vit D deficiency compared to stabilized outpatients. The cohort (152 total patients, 75 males and 77 females) had a mean age of 47.3 ± 14.4 years at admission and was grouped according to psychiatric diagnosis. Psychopathological symptom severity was assessed by the Brief Psychiatric Rating Scale (BPRS), a multidimensional symptom inventory. Total calcium serum levels were measured using standard laboratory methods, while plasma levels of 25-OH-Vit D and parathyroid hormone (PTH) were measured by automated chemiluminescence immunoassays. The psychiatric inpatient subgroup showed a significant difference in serum levels of 25-OH-Vit D and PTH (p < 0.001). Correlation analysis between serum levels of 25-OH-Vit D and BPRS total and subitem scores indicated a significantly negative relationship. In addition, linear regression analysis evidenced that the inpatient condition might predict low PTH and 25-OH-Vit D serum levels. Hospitalized psychiatric patients are at increased risk for Vit D deficiency regardless of their diagnostic categories. The mechanism underlying the association between acute psychiatric relapses and Vit D deficiency remains unclear. Therefore, screening for Vit D deficiency should pertain to the health assessment of patients with major psychiatric disorders.