Cariprazine Augmentation in Treatment-Resistant Bipolar Depression: Data from a Retrospective Observational Study.

BACKGROUND: Treatment-resistant bipolar depression is one of the leading problems in psychiatry with serious consequences on patients functioning, quality of life and resource utilization. Despite this, there is a lack of consensus on diagnostic criteria and treatment algorithms. OBJECTIVE: The objective of the present study is to assess the acute effectiveness and tolerability of cariprazine in the management of treatment resistant bipolar depression. METHODS: This is a four weeks retrospective multicentric observational study on patients with treatment resistant bipolar depression receiving cariprazine in augmentation to the current treatment. Cariprazine dosage changed during the follow-up period according to clinical judgment. Since data followed a non-normal distribution, non-parametric tests were used to pursue the analysis. The effectiveness of cariprazine was assessed through the mean change in Hamilton Depression rating scale (HAM-D) scores from baseline to endpoint. For missing values, a "Last Observation Carried Forward" approach was applied. RESULTS: Fifty-one patients were enrolled. Four patients (7.8%) discontinued cariprazine mainly due to adverse events. Mean cariprazine dose was 1.7 mg/day. The mean HAM-D score decreased significantly from baseline (T0) to week 4 (T4) at each evaluation point. Fourty-five.one per cent of the patients benefited of cariprazine add-on strategy: 23.5% achieved a clinical response and 21.6% were remitters. Among the completers, 70.6% experienced at least one adverse event. All side effects were mild to moderate. CONCLUSION: Cariprazine seems to be an effective and well tolerated option in the management of patients with treatment resistant bipolar depression.

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations.

Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders.

Brexpiprazole for treatment-resistant major depressive disorder.

Introduction:Treatment-resistant depression (TRD), seldom interchangeably referred to as 'depression inadequately responding to the standard antidepressant drug,' carries a significant burden. The atypical antipsychotics represent a popular augmentation strategy for antidepressant-resistant depression, although their efficacy/safety profiles vary across different agents and presentations of depression. Areas covered: This review appraises the evidence supporting the use of brexpiprazole augmentation for major depressive disorder (MDD) adults showing an inadequate response to standard antidepressants, covering the related regulatory affairs, and essential pharmacology. Expert opinion: Brexpiprazole is a 'third-generation' antipsychotic featuring dopaminergic D2 and serotonergic 5-HT1A partial agonism approved by the U.S. Food and Drug Administration for the treatment of MDD, besides schizophrenia in adults. The clinical trials leading to the extended approval of brexpiprazole rely on the definition of 'inadequate response' to antidepressants, which seems to poorly represent the most severe cases of TRD seen in clinical practice. TRD definitions appraised in the literature are likewise inconsistent and questionable from a clinical-standpoint. Compared to aripiprazole, brexpiprazole has lower D2 intrinsic activity, although the latter features a more potent serotonergic 5-HT2A antagonism. The actual propensity of brexpiprazole to induce akathisia and tardive dyskinesia warrants assessment by ad-hoc designed long-term, controlled trials.

The identification of biomarkers predicting acute and maintenance lithium treatment response in bipolar disorder: A plea for further research attention.

The prediction of acute and maintenance lithium treatment response carries major clinical and neurobiological implications, warranting systematic review. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant review searched major electronic databases from inception until December 2017 for studies documenting a clinical diagnosis of bipolar disorder (BD) made according to the mainstream diagnostic manuals and confirmed by a structured interview. Eligible studies allowed a quantitative comparison of endpoint vs baseline mean values of a given biomarker, regardless of the mood phase of patients with BD, and the disorder was assessed for severity using validated rating tool(s). Owing to the purposely applied stringent selection criteria, 16 acute and 12 maintenance studies could be included. The anticipated publication bias limited the chances of reportable generalizable findings, hindering a side-by-side comparison of different records across varying biomarkers and subsequent meta-analyses. The PRISMA approach was nonetheless preferred; it aimed at enhancing the homogeneity of the included results and minimizing the chances of "apples and oranges" with respect to the present research theme. The present critical review confirms the need for future research to specifically assess either pretreatment and/or posttreatment putative biomarkers of patients with BD and treated with lithium.

Vortioxetine exerts anti-inflammatory and immunomodulatory effects on human monocytes/macrophages.

BACKGROUND AND PURPOSE: A crosstalk between the immune system and depression has been postulated, with monocytes/macrophages and cytokines having a key role in this interaction. In this study, we examined whether vortioxetine, a multimodal anti-depressive drug, was endowed with anti-inflammatory and antioxidative activity, leading to immunomodulatory effects on human monocytes and macrophages. EXPERIMENTAL APPROACH: Human monocytes were isolated from buffy coats and used as such or differentiated into M1 and M2 macrophages. Cells were treated with vortioxetine before or after differentiation, and their responsiveness was evaluated. This included oxy-radical and TNFα production, TNFα and PPARγ gene expression and NF-κB translocation. KEY RESULTS: Vortioxetine significantly reduced the PMA-induced oxidative burst in monocytes and in macrophages (M1 and M2), causing a concomitant shift of macrophages from the M1 to the M2 phenotype, demonstrated by a significant decrease in the expression of the surface marker CD86 and an increase in CD206. Moreover, treatment of monocytes with vortioxetine rendered macrophages derived from this population less sensitive to PMA, as it reduced the oxidative burst, NF-kB translocation, TNFα release and expression while inducing PPARγ gene expression. FACS analysis showed a significant decrease in the CD14+ /CD16+ /CD86+ M1 population. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that in human monocytes/macrophages, vortioxetine has antioxidant activity and anti-inflammatory effects driving the polarization of macrophages towards their alternative phenotype. These findings suggest that vortioxetine, alongside its antidepressive effect, may have immunomodulatory properties.

Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: Essential review of the literature and case report.

RATIONALE: Valproic Acid is a commonly used psychiatric drug primarily used as a mood stabilizer. Mild hyperammonemia is a Valproic Acid common adverse effect. This report presents an example of treated hyperammonemia on Valproic acid therapy managed with L-carnitine administration in BD patients characterized by sudden vulnerability. PATIENT CONCERNS: We report the case of a 29-year-old man suffering from bipolar disorder (BD) and substance use disorder who exhibited sudden altered mental status upon admittance to the inpatient unit. The patient was started on Valproic acid with no improvement. DIAGNOSES: The patient had remarkably high ammonia levels (594 µg/dL) without hepatic insufficiency, likely due to his valproate treatment. INTERVENTIONS: The patient was administered lactulose, intravenous hydration, and i.v. levocarnitine supplementation 4.5 g/day. OUTCOMES: The administration leads to reduction of ammonia levels to 99 µg/dL within 12 hours upon initiation of carnitine therapy and progressive restore of his mental status within 24 hours. LESSONS: Resolution of hyperammonemia caused by Valproic acid therapy may be enhanced with the administration of L-carnitine. An interesting aspect of this case was how rapidly the patient responded to the carnitine therapy.

Immigrants' Pathways to Outpatient Mental Health: Are there Differences with the Native Population?

A poor use of mental health services has been described in immigrants. We compared the sociodemographic, clinical and treatment features of immigrants and natives attending a Community Mental Health Centre (CMHC). 191 immigrants and 191 randomly selected natives applying to the Borgomanero CMHC between 1 January 2003 and 31 August 2013 were compared. Our sample consisted mainly of the so-called "economic" immigrant. Adjustment disorders and reaction to stress were the most frequent diagnoses; in most cases symptoms onset occurred after migration. Although treatment features overlapped in the two groups (duration, number of contacts), immigrants showed a higher frequency of treatment dropout. While it is necessary to improve access to mental health services for immigrants, for the "economic" immigrant it may be more important to focus on establishing a therapeutic relationship that can be experienced as reliable and trustworthy. The finding of similar pathways to access the CMHC in natives and immigrants is encouraging.

Neurokinin (NK)-1 receptor expression in monocytes from bipolar disorder patients: a pilot study.

BACKGROUND: Neurokinin 1 receptors (NK-1R) have been involved in several psychiatric disorders including major depression, but less is known for bipolar disorder (BD). METHOD: We compared NK-1R expression and Substance P (SP) ability to induce NF-κB activation in monocytes from BD patients and healthy donors (HD), also looking for the effects of tobacco smoke. After informed written consent, 20 euthymic BD patients, either bipolar type 1 (BDI) or type 2 (BDII), and 14 age-matched healthy donors (HD) were enrolled. NK-1R expression in monocytes was evaluated by Western blot and expressed as the ratio between NK-1R and Na(+)/K(+)-ATPase protein expressions. NF-κB activation was assessed by measuring the nuclear content of the p50 subunit (ELISA kit). RESULTS: NK-1R expression was significantly reduced (P<0.001) in monocytes from BD patients as compared to HD, with no major differences between BDI and BDII patients. Tobacco smoke enhanced NK-1R expression in HD, but not in BD patients. Un-stimulated monocytes from BD patients presented a constitutively higher (P<0.05) content of nuclear p50 subunit as compared to HD. SP and an NK-1R agonist induced NF-κB activation, with a higher effect in HD: this effect was receptor-mediated as it was abrogated by an NK-1R antagonist. LIMITATIONS: As a pilot study enrolling 20 BD patients, an obvious limitation is the sample size. CONCLUSIONS: Our results show the existence of a relevant alteration in NK-1R expression in BD patients and further suggest SP involvement in BD, so improving our understanding of the underlying mechanisms of this disease.

Factor structure and reliability of the Italian adaptation of the Hypomania Check List-32, second revision (HCL-32-R2).

OBJECTIVE: To assess the psychometric properties of the Italian adaptation of the Hypomania-Check-List 32-item, second revision (HCL-32-R2) for the detection of bipolarity in major depressive disorder (MDD) treatment-seeking outpatients. METHODS: A back-to-back Italian adaption of the "Bipolar Disorders: Improving Diagnosis, Guidance, and Education" English module of the HCL-32-R2 was administered between March 2013 and October 2014 across twelve collaborating sites in Italy. Diagnostic and Statistical Manual Fourth edition (DSM-IV) diagnoses were made adopting the mini-international neuropsychiatric interview, using bipolar disorder (BD) patients as controls. RESULTS: In our sample (n=441, of whom, BD-I=68; BD-II=117; MDD=256), using a cut-off of 14 allowed the HCL-32-R2 to discriminate DSM-IV-defined MDD patients between "true unipolar" (HCL-32-R2(-)) and "sub-threshold bipolar depression" (HCL-32-R2(+)) with sensitivity=89% and specificity=79%. Area under the curve was .888; positive and negative predictive values were 75.34% and 90.99% respectively. Owing to clinical interpretability considerations and consistency with previous adaptations of the HCL-32, a two-factor solution (F1="hyperactive/elated" vs. F2="irritable/distractible/impulsive") was preferred using exploratory and confirmatory factor analyses, whereas items n.33 ("I gamble more") and n.34 ("I eat more") introduced in the R2 version of the scale slightly loaded onto F2 and F1 respectively. Cronbach׳s α=.88 for F1 and .71 for F2. LIMITATIONS: No cross-validation with any additional validated screening tool; treatment-seeking outpatient sample; recall bias; no systematic evaluation of eventual medical/psychiatric comorbidities, current/lifetime pharmacological history, neither record of severity of current MDE. CONCLUSIONS: Our results seem to indicate fair accuracy of HCL-32 as a screening instrument for BD, though replication studies are warranted.

Treatment adherence towards prescribed medications in bipolar-II acute depressed patients: relationship with cyclothymic temperament and "therapeutic sensation seeking" in response towards subjective intolerance to pain.

BACKGROUND: Treatment adherence (TA) is crucial during almost any phase of bipolar disorder (BD), including type-II (BD-II) acute depression. While a number of issues have been traditionally accounted on the matter, additional factors should be likewise involved, including affective temperaments and some clinically suggestive psychopathological traits whose systematic assessment represents the aim of this study. METHODS: Two hundred and twenty BD-II acute depressed outpatients were consecutively evaluated using the Structured Clinical Interviews for Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition Axis-I and II Disorders, Hamilton scales for Depression and Anxiety, Temperament Evaluation of the Memphis Pisa Paris San Diego-Auto-questionnaire-110-item, Visual Analogue Scale (VAS), Zuckerman's Sensation-Seeking Scale-Form-V (SSS-V), Barratt's Impulsivity Scale-11-item, State-Trait Anxiety Inventory modules, Severity module of the Clinical Global Impression Scale for BD, Morisky 8-Item Medication Adherence Scale (MMAS-8) and the Clinician Rating Scale (CRS). Patients were divided into non-adherent vs. treatment-adherent cases depending on MMAS-8+CRS scores. RESULTS: In the TA(-) group, higher VAS and cyclothymic temperament scores were highly correlated (r=.699; p≤.001). Those latter scores, along with SSS-V scores and the occurrence of lifetime addiction to painkiller and/or homeopathic medications available over the counter defined a "therapeutic sensation seeking" pattern allowing to correctly classify as much as 93.9% [Exp(B)=3.490; p≤.001] of TA(-) cases (49/220). LIMITS: Lack of objective TA measures and systematic pharmacological record; recall bias on some diagnoses; and relatively small sample size. CONCLUSIONS: Stating the burden of TA in BD, additional studies on this regard are aimed, ideally contributing to enhance the management of BD itself.

Adjunctive agomelatine therapy in the treatment of acute bipolar II depression: a preliminary open label study.

PURPOSE: The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for melatonin in regulating mood, thus extending the interest toward the melatonergic antidepressant agomelatine as well as type I (acute) or II cases of bipolar depression. PATIENTS AND METHODS: Twenty-eight depressed BD-II patients received open label agomelatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or valproate, followed by an optional treatment extension of 30 weeks. Measures included the Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression Scale-Bipolar Version, Young Mania Rating Scale, and body mass index. RESULTS: Intent to treat analysis results demonstrated that 18 of the 28 subjects (64%) showed medication response after 6 weeks (primary study endpoint), while 24 of the 28 subjects (86%) responded by 36 weeks. When examining primary mood stabilizer treatment, 12 of the 17 (70.6%) valproate and six of the 11 (54.5%) lithium patients responded by the first endpoint. At 36 weeks, 14 valproate treated (82.4%) and 10 lithium treated (90.9%) subjects responded. At 36 weeks, there was a slight yet statistically significant (P = 0.001) reduction in body mass index and Pittsburgh Sleep Quality Index scores compared to respective baseline values, regardless of mood stabilizer/outcome. Treatment related drop-out cases included four patients (14.28%) at week 6 two valproate-treated subjects with pseudo-vertigo and drug-induced hypomania, respectively, and two lithium-treated subjects with insomnia and mania, respectively. Week 36 drop outs were two hypomanic cases, one per group. CONCLUSION: Agomelatine 25 mg/day was an effective and well-tolerated adjunct to valproate/lithium for acute depression in BD-II, suggesting the need for confirmation by future double blind, controlled clinical trials.

Sensation seeking in major depressive patients: relationship to sub-threshold bipolarity and cyclothymic temperament.

BACKGROUND: High levels of sensation seeking (SS) have been traditionally reported for lifetime bipolar disorder (BD) and/or substance use disorder (SUD) rather than major depressive disorder (MDD). Nonetheless, a renewed clinical attention toward the burden of sub-threshold bipolarity in MDD, solicits for a better assessment of "unipolar" major depressive episodes (MDEs) via characterization of putative differential psychopathological patterns, including SS and predominant affective temperament. METHODS: Two hundred and eighty currently depressed cases of MDD and 87 healthy controls were screened using the Zuckerman's sensation seeking scale-Form-V, the Hypomania Check List-32-item (HCL-32), the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto-questionnaire-110-item, the Barratt Impulsivity Scale-11-item, the State-Trait Anxiety Inventory modules and the Structured Clinical Interview for DSM-IV axis-I disorders. Cases were divided into HCL-32(+)(sub-threshold bipolar)/HCL-32(-)("true" unipolar depressed) depending on the HCL-32 total score. RESULTS: Upon correlation and multivariate regression analyses, the HCL-32(+) patients showed the highest levels of SS, higher prevalence of cyclothymic temperament, and higher rates of multiple lifetime axis-I co-morbidities, including SUD. LIMITS: Recall bias on some diagnoses, including BD, grossly matched healthy control group, lack of ad-hoc validated measures for ADHD, SUD, or axis-II disorders. CONCLUSIONS: In our sample, the occurrence of higher levels of SS in "sub-threshold" bipolar cases outlined a differential psychopathological profile compared to DSM-defined "true unipolar" cases of MDE. If confirmed by replication studies, these findings may aid clinicians in delivering a more accurate diagnosis and a safer use of antidepressants in some MDD cases.

Risperidone-associated hyperprolactinemia: evaluation in twenty psychiatric outpatients.

Despite the lack of extrapyramidal side effects, some atypical antipsychotics can induce an increase in prolactinemia, as the conventional neuroleptics do. We decided to evaluate the effects of risperidone on serum prolactin levels and prolactin-related adverse effects in 20 outpatients of an Italian community psychiatric service. Patients enrolled in this study were on risperidone (2-8 mg per day; mean dose=4.15+/-0.4 mg per day) treatment in the period May-November 2002. The 20 patients, 13 women and 7 men (mean age=36.38+/-3.2 years for women and 29.7+/-2.2 for men) who accomplished inclusion criteria, participated in the study after giving informed written consent. Raised prolactin levels were observed in 13 (9 women and 4 men) out of 20 patients, but only 8 patients presented prolactin-related adverse effects, libido reduction being the most frequent. In this observational study, risperidone enhanced serum prolactin in 65% of patients. A good correlation was found between age and prolactin levels in pre-menopausal women, although no clear correlation among duration of treatment, dose used, prolactin levels and prolactin-related adverse effects could be established.