Efficacy and safety of ketamine and esketamine for unipolar and bipolar depression: an overview of systematic reviews with meta-analysis.

Background: Unipolar and bipolar depression present treatment challenges, with patients sometimes showing limited or no response to standard medications. Ketamine and its enantiomer, esketamine, offer promising alternative treatments that can quickly relieve suicidal thoughts. This Overview of Reviews (OoR) analyzed and synthesized systematic reviews (SRs) with meta-analysis on randomized clinical trials (RCTs) involving ketamine in various formulations (intravenous, intramuscular, intranasal, subcutaneous) for patients with unipolar or bipolar depression. We evaluated the efficacy and safety of ketamine and esketamine in treating major depressive episodes across various forms, including unipolar, bipolar, treatment-resistant, and non-resistant depression, in patient populations with and without suicidal ideation, aiming to comprehensively assess their therapeutic potential and safety profile. Methods: Following PRIOR guidelines, this OoR's protocol was registered on Implasy (ID:202150049). Searches in PubMed, Scopus, Cochrane Library, and Epistemonikos focused on English-language meta-analyses of RCTs of ketamine or esketamine, as monotherapy or add-on, evaluating outcomes like suicide risk, depressive symptoms, relapse, response rates, and side effects. We included studies involving both suicidal and non-suicidal patients; all routes and formulations of administration (intravenous, intramuscular, intranasal) were considered, as well as all available comparisons with control interventions. We excluded meta-analysis in which the intervention was used as anesthesia for electroconvulsive therapy or with a randomized ascending dose design. The selection, data extraction, and quality assessment of studies were carried out by pairs of reviewers in a blinded manner. Data on efficacy, acceptability, and tolerability were extracted. Results: Our analysis included 26 SRs and 44 RCTs, with 3,316 subjects. The intervention is effective and well-tolerated, although the quality of the included SRs and original studies is poor, resulting in low certainty of evidence. Limitations: This study is limited by poor-quality SRs and original studies, resulting in low certainty of the evidence. Additionally, insufficient available data prevents differentiation between the effects of ketamine and esketamine in unipolar and bipolar depression. Conclusion: While ketamine and esketamine show promising therapeutic potential, the current evidence suffers from low study quality. Enhanced methodological rigor in future research will allow for a more informed application of these interventions within the treatment guidelines for unipolar and bipolar depression. Systematic review registration: [https://inplasy.com/inplasy-2021-5-0049/], identifier (INPLASY202150049).

Chronotype and Cardiometabolic Parameters in Patients with Bipolar Disorder: Preliminary Findings.

Cardiometabolic alterations are very common in bipolar disorder (BD). The aim of this study was to investigate the relationship between chronotype and cardiometabolic parameters in patients with a primary diagnosis of BD. This study is an observational clinical investigation including 170 subjects consecutively admitted to the Psychiatric Inpatient Unit of the IRCCS Ospedale Policlinico San Martino (Genoa, Italy), recruited over a period of 48 months. A psychometric tool assessing chronotype was administered and blood tests were performed. Furthermore, the atherogenic coefficient ((total cholesterol-HDL cholesterol)/HDL cholesterol), and Castelli risk index-I (total cholesterol/HDL cholesterol) and -II (LDL cholesterol/HDL cholesterol) were calculated. Patients with BD and an eveningness chronotype showed a higher body mass index, total and low-density lipotrotein cholesterol compared to patients with BD and an intermediate or morning chronotype. Furthermore, the Atherogenic Coefficient and Castelli Risk-Index I-II were found to be higher in bipolar patients with an evening chronotype. The role of chronotype in the development of obesity and cardiovascular risk is, therefore, a relationship worth being investigated, especially in the context of BD, to ameliorate the clinical and therapeutic approach, aiming at increasing the quality of life and reducing the mortality.

Personality Traits and Fatigue in Multiple Sclerosis: A Narrative Review.

(1) Background: Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease. Fatigue is a prevalent and debilitating symptom that significantly impacts the quality of life of these patients. A relationship between personality traits and fatigue in MS has been hypothesized but not clearly defined. (2) Methods: A literature search was carried out from databases up to April 2023 for studies correlating personality traits and fatigue in patients suffering from MS. (3) Results: A total of ten articles was included; most of the studies depict a neuroticism-fatigue correlation; however, they were not consistent in terms of the fatigue, personality, and covariate assessments. (4) Conclusions: The clinical and methodological heterogeneity of the included studies prevented us from drawing any firm conclusion on the link between personality traits and fatigue in MS. Several models of personality and different fatigue assessments have been found. Despite this, a common pathway shows that the neuroticism trait or similar personality patterns has a role in fatigue diagnosis. This may be a useful target to improve the quality of life and enhance the modification of the disease treatment results. Further homogeneous and longitudinal studies are needed.

The Role of Gender in Patients with Borderline Personality Disorder: Differences Related to Hopelessness, Alexithymia, Coping Strategies, and Sensory Profile.

Background and Objectives: Gender differences are poorly investigated in patients with borderline personality disorder (BPD), although they could be useful in determining the most appropriate pharmacological and non-pharmacological treatment. The aim of the present study was to compare sociodemographic and clinical characteristics and the emotional and behavioral dimensions (such as coping, alexithymia, and sensory profile) between males and females with BPD. Material and Methods: Two hundred seven participants were recruited. Sociodemographic and clinical variables were collected through a self-administered questionnaire. The Adolescent/Adult Sensory Profile (AASP), Beck Hopelessness Scale (BHS), Coping Orientation to Problems Experienced (COPE), and Toronto Alexithymia Scale (TAS-20) were administered. Results: Male patients with BPD showed more involuntary hospitalizations and greater use of alcohol and illicit substances compared to females. Conversely, females with BPD reported more frequent medication abuse than males. Furthermore, females had high levels of alexithymia and hopelessness. Regarding coping strategies, females with BPD reported higher levels of "restraint coping" and "use of instrumental social support" at COPE. Finally, females with BPD had higher scores in the Sensory Sensitivity and Sensation Avoiding categories at the AASP. Conclusions: Our study highlights gender differences in substance use, emotion expression, future vision, sensory perception, and coping strategies in patients with BPD. Further gender studies may clarify these differences and guide the development of specific and differential treatments in males and females with BPD.

Neurobiology and Applications of Inositol in Psychiatry: A Narrative Review.

Inositol is a natural sugar-like compound, commonly present in many plants and foods. It is involved in several biochemical pathways, most of them controlling vital cellular mechanisms, such as cell development, signaling and nuclear processes, metabolic and endocrine modulation, cell growth, signal transduction, etc. In this narrative review, we focused on the role of inositol in human brain physiology and pathology, with the aim of providing an update on both potential applications and current limits in its use in psychiatric disorders. Overall, imaging and biomolecular studies have shown the role of inositol levels in the pathogenesis of mood disorders. However, when administered as monotherapy or in addition to conventional drugs, inositol did not seem to influence clinical outcomes in both mood and psychotic disorders. Conversely, more encouraging results have emerged for the treatment of panic disorders. We concluded that, despite its multifaceted neurobiological activities and some positive findings, to date, data on the efficacy of inositol in the treatment of psychiatric disorders are still controversial, partly due to the heterogeneity of supporting studies. Therefore, systematic use of inositol in routine clinical practice cannot be recommended yet, although further basic and translational research should be encouraged.

Complex polypharmacy in bipolar disorder: Results from a real-world inpatient psychiatric unit.

BACKGROUND: Multiple medications are frequently prescribed to patients with bipolar disorder (BD). The aim of the present study was to identify sociodemographic and clinical characteristics associated with complex polypharmacy in patients affected by BD. METHODS: 556 patients with BD were included. A semi-structured interview was used to collect sociodemographic and clinical characteristics, as well as pharmacological treatment. Participants were divided in two groups, abased on the use of complex polypharmacy (i.e., a combination of 4 or more psychotropic medications). Differences between the two groups were evaluated with t-test and chi-squared test. A stepwise logistic regression was then applied to identify factors significantly associated with complex polypharmacy. RESULTS: Patients with BD and complex polypharmacy were more likely to be single and unemployed. Moreover, earlier age at onset, longer duration of illness, higher number of hospitalizations, higher prevalence of medical and psychiatric comorbidity, and the use of illicit substances (except heroin) were associated with complex polypharmacy. In the logistic regression model, single status, older age, number of hospitalizations, and the presence of psychiatric comorbidities were regarded as factors significantly associated with complex polypharmacy. CONCLUSIONS: Our findings reflect the need to develop clear guidelines for the long-term management of BD, especially when pharmacological discontinuation is needed.

C-Reactive Protein as a Potential Peripheral Biomarker for High-Lethality Suicide Attempts.

The aim of the present study was to identify a cut-off of c-reactive protein (c-RP) potentially predictive of high-lethality suicide attempts (SA) in an inpatient psychiatric sample. After attempting suicide, subjects were admitted to the emergency ward of the IRCCS Ospedale Policlinico San Martino and later to the section of Psychiatry from 1 August 2013 to 31 July 2018. C-reactive protein was measured. The Area Under the Receiver Operating Characteristic (ROC_AUC) was used to assess the discriminative capacity of c-RP for high- vs. low-lethality SA, and a logistic regression was performed to detect the odds ratio, adjusted for age and sex. High-lethality suicide attempters were 133 (30.8%), while low-lethality suicide attempters were 299 (69.2%). The optimal cut-off threshold (and corresponding sensitivity and specificity values) for c-RP was 4.65 mg/L (68/71%). This cut-off corresponds to an AUC of 73.5%. An odds ratio of 4.70 was generated for current high-lethality SA after a logistic regression, adjusted for age and sex. Research on social and biological factors underlying the lethality of SA is crucial for a better understanding of this complex phenomenon. Identifying potential predictors of SA, especially those at high lethality, is essential to implement personalized preventive strategies.

Bipolar Disorder and Polysubstance Use Disorder: Sociodemographic and Clinical Correlates.

Introduction: Patients with bipolar disorder (BD) often show comorbidity with substance use disorder (SUD) with a negative impact on clinical course, prognosis, and functioning. The role of polysubstance use disorder (polySUD) is understudied. The aim of the present paper is to evaluate the sociodemographic and clinical characteristics associated with BD and comorbid SUD, focusing on polySUD, in order to phenotype this specific group of patients and implement adequate treatment and prevention strategies. Methods: A cross-sectional study was conducted involving 556 patients with a primary diagnosis of BD (376 without SUD, 101 with SUD, and 79 with polySUD). A semi-structured interview was administered to collect sociodemographic variables, clinical characteristics, and pharmacological treatment. ANOVA and chi-square tests were used to compare the three groups. Significantly different variables were then inserted in multivariate logistic regression. Results: Patients affected by BD and polySUD were younger, and more frequently males and single, than patients with SUD or without SUD. Indeed, the prevalence of patients affected by BD and polySUD living in residential facilities was higher than in the other groups. Moreover, earlier age at onset, higher prevalence of psychotic and residual symptoms, involuntary hospitalization, and a family history of psychiatric disorders were associated with polySUD in patients suffering from BD. Lastly, patients with BD and polySUD were more likely to take four or more medications, particularly benzodiazepines and other drugs. At the multinomial regression, younger age, male gender, early age at onset, psychotic and residual symptoms, positive family history of psychiatric disorders, and use of benzodiazepines remained significantly associated with polySUD in patients with BD. Conclusion: Our findings show a specific profile of patients with BD and polySUD. It is important to conduct research on this topic in order to adopt specific therapeutic strategies, minimize the use of polypharmacy, and aim at full remission and mood stabilization.

Factors Associated with Medication Adherence to Long-Acting Injectable Antipsychotics: Results from the STAR Network Depot Study.

INTRODUCTION: Long-acting injectable (LAI) antipsychotics are prescribed to people with severe psychiatric disorders who show poor adherence to oral medication. The present paper examined factors potentially associated with medication adherence to LAI treatment. METHODS: The STAR (Servizi Territoriali Associati per la Ricerca) Network Depot Study was a multicenter, observational, prospective study that enrolled 461 subjects initiating a LAI from 32 Italian centers. After 6 and 12 months of treatment, we evaluated differences between participants with high (≥5 points) and low (<5 points) medication adherence using Kemp's 7-point scale in sociodemographic, clinical, psychopathological, and drug-related variables. Factors that differed significantly between the two groups were entered for multivariate logistic regression. RESULTS: Six months after enrollment, participants with high medication adherence were younger, living with other people, had lower Brief Psychiatric Rating Scale (BPRS) total scores, lower adverse events, and a more positive attitude toward medication than participants with low adherence. Multivariate regression confirmed lower BPRS resistance and activation scores, absence of adverse events, and positive attitude toward medication as factors significantly associated with good adherence. After 12 months, all BPRS subscales were significantly lower in the high adherence group, which also showed a more positive attitude toward medication. BPRS resistance and attitude toward medication were confirmed as factors associated with medication adherence. DISCUSSION: Our findings suggest that adherence to LAI is principally related to attitude toward medication and traits of suspiciousness/hostility. Quality of patient-clinician relationship and tailored psychoeducational strategies may positively affect adherence in people undergoing psychopharmacological treatment, including LAI.

Risk Perception among Psychiatric Patients during the COVID-19 Pandemic.

The fear of the new coronavirus infection has driven many non-COVID-19 patients away from essential healthcare. Our study aimed to investigate the perception of risk and feelings of danger for the contagion in a sample of Italian psychiatric patients. We conducted a cross-sectional observational study during the second wave of the COVID-19 pandemic and the lockdown in Italy. The risk perception and risk-related variables were assessed in a sample of 150 consecutive patients with a previous diagnosis of major depression (50), bipolar I disorder (50), and schizophrenia seeking ambulatory care using a questionnaire previously administered to the general Italian population. Our results showed that patients were more concerned about economic, psychological, and interpersonal consequences of COVID-19 pandemic, rather than about their own health. At the multiple regression analysis, the likelihood of COVID-19 resolution was positively influenced by the diagnosis of schizophrenia, the increased perceived effectiveness, and the presence of positive emotions. Indeed, positive emotions and uncertainty positively influenced interpersonal risk. Our study highlights the need to provide more support to psychiatric patients during emergency events to prevent them from engaging in risky behaviors.

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.

Gender Differences in Complete Blood Count and Inflammatory Ratios among Patients with Bipolar Disorder.

Background: Evidence suggested that inflammation may be involved in the etiopathogenesis of bipolar disorder (BD), a chronic psychiatric condition affecting around 2-3% of the general population. However, little is known regarding potential gender differences in peripheral biomarkers of BD, such as neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and monocyte-to-lymphocyte (MLR) ratios. Methods: In total, 197 females and 174 males with BD in different phases (i.e., (hypo)mania, depression, euthymia) were recruited. A blood sample was drawn to perform a complete blood count (CBC). NLR, PLR, and MLR were subsequently calculated, and differences were computed according to the illness phase and gender. Results: PLR was consistently higher in (hypo)manic than depressed patients, in both males and females. No significant gender differences in PLR value were found when considering only (hypo)mania. Conversely, NLR was increased in (hypo)mania only among males, and gender differences were retrieved in the (hypo)manic subgroup. The findings related to MLR were only marginally significant. Higher platelets values were associated with (hypo)mania only in the female group. Basophils and eosinophils appeared gender- but not state-dependent. Conclusions: Our findings provide further evidence that increased PLR levels may be associated with (hypo)mania in bipolar patients, regardless of gender. Moreover, the usefulness of NLR as a peripheral biomarker of BD appeared limited to males while the role of platelets to females. As CBC represents a low-cost and easily accessible test, researchers should investigate in-depth its potential usefulness as a biomarker of BD and other psychiatric disorders.

Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte and Monocyte-to-Lymphocyte Ratio in Bipolar Disorder.

BACKGROUND: Several inflammatory hypotheses have been suggested to explain the etiopathogenesis of bipolar disorder (BD) and its different phases. Neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and monocyte-to-lymphocyte (MLR) ratios have been proposed as potential peripheral biomarkers of mood episodes. METHODS: We recruited 294 patients affected by BD, of which 143 were experiencing a (hypo)manic episode and 151 were in a depressive phase. A blood sample was drawn to perform a complete blood count. NLR, PLR, and MLR were subsequently calculated. A t-test was performed to evaluate differences in blood cell counts between depressed and (hypo)manic patients and a regression model was then computed. RESULTS: Mean values of neutrophils, platelets, mean platelet volume, NLR, PLR, and MLR were significantly higher in (hypo)manic than depressed individuals. Logistic regression showed that PLR may represent an independent predictor of (hypo)mania. CONCLUSIONS: Altered inflammatory indexes, particularly PLR, may explain the onset and recurrence of (hypo)manic episodes in patients with BD. As inflammatory ratios represent economical and accessible markers of inflammation, further studies should be implemented to better elucidate their role as peripheral biomarkers of BD mood episodes.

Second-to-Fourth Digit Ratio (2D:4D) in Psychiatric Disorders: A Systematic Review of Case-control Studies.

The second-to-fourth digit ratio (2D:4D) is an indirect, retrospective, non-invasive measure that correlates negatively with intrauterine exposure to testosterone. The present meta-analysis aimed to evaluate if 2D:4D differs between patients with psychiatric disorders and controls. In September 2019, we searched in Web of Knowledge, PsycINFO, Embase, and CINHAL, and retrieved 619 papers. We finally included 43 case-control studies which compared the 2D:4D ratio of patients with autism spectrum disorder (ASD) (n = 16), schizophrenia (n = 8), gender non-conformity (n = 7), addictions (n = 5), attention deficit-hyperactivity disorder (ADHD) (n = 4), mood disorders (n = 2), and intellectual disability (n = 1) to non-clinical controls. Meta-analyses showed that, overall, psychiatric patients had lower 2D:4D than healthy controls (n = 43, overall sample = 9,484, mean difference = -0.0056, 95% confidence interval from -0.0093 to -0.002, I2 = 74%), with more pronounced differences in the right hand, males, and children. Considering psychiatric disorders individually, significant differences were found in the ASD, ADHD, and addictions groups, in which 2D:4D was significantly lower than healthy controls. Conversely, the right hand of males with schizophrenia showed higher 2D:4D than healthy controls. No other significant differences were detected. Although our results need to be cautiously interpreted and find limited applications in clinical practice, they may suggest that 2D:4D is altered in some psychopathological conditions, underlining the role of prenatal exposure to sex steroids in the etiology of psychiatric disorders.

Vitamin D and Depressive Symptoms in Adults with Multiple Sclerosis: A Scoping Review.

BACKGROUND: Vitamin D deficiency has been correlated with Multiple Sclerosis (MS) risk and disease activity. There is some controversy as to whether vitamin D could have an impact on depressive symptoms in people with MS (pwMS). The aim of this scoping review was to evaluate the association between vitamin D status and depressive symptoms in pwMS. METHODS: We searched databases to include studies published up to March 2021 to provide an overview of the available evidence on the correlation between vitamin D status and depressive symptoms in pwMS. The eligibility criteria were as follows: studies evaluating the use of vitamin D measurement on depressive symptoms in patients suffering from MS, including randomized and non-randomized studies; studies written in English; and studies exploring an adult population over the age of 18. RESULTS: Eleven studies met our inclusion criteria: two of them were abstracts only; the majority were cross-sectional studies; two were prospective longitudinal studies; one was a retrospective cohort study; and one was a randomized placebo-controlled trial (RCT). Of the eleven studies selected, seven showed a potential correlation between low vitamin D levels and depressive symptoms. CONCLUSION: Future RCT studies should include patients with greater severity of depressive symptoms and should consider confounding factors such as sun exposure and seasonal variation of vitamin D.

Lipid and Glycemic Profiles in Patients with Bipolar Disorder: Cholesterol Levels Are Reduced in Mania.

Background and Objectives: Bipolar disorder (BD) is a severe mental condition with a lifetime prevalence estimated around 2% among the general population. Due to risk factors, etiological mechanisms, and the chronic use of psychotropic medications, people with BD are frequently affected by medical comorbidities, such as metabolic syndrome (MetS), associated with altered blood levels of glucose, cholesterol, and triglycerides. Moreover, the lipid concentration may be associated with the severity of psychiatric symptoms. Materials and Methods: Five hundred and forty-two in- and outpatients (418 affected by BD and 124 affected by schizophrenia) were recruited in two Italian university hospitals. A blood examination assessing the fasting glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides was performed. Results: No significant differences were found in the lipid and glycemic profiles between patients with BD and schizophrenia. When considering only the BD sample, we found that patients experiencing a manic episode had significantly lower total cholesterol, HDL, and LDL than euthymic patients. Moreover, the total and LDL cholesterol levels were significantly lower in (hypo)manic than depressed patients. Mood episodes did not influence the triglyceride and glucose levels in our sample. Conclusions: Clinicians should pay attention to blood cholesterol levels in patients with BD, as differences in concentrations may predispose them to severe medical conditions and can be associated with the onset of mood episodes.