Ilaria Cuomo

An improved simple LC–MS/MS method for the measurement of serum aripiprazole and its major metabolite

BACKGROUND AND OBJECTIVES Current liquid chromatographic tandem mass spectrometry (LC-MS/MS) methods to measure serum levels of aripiprazole (Ar) and dehydroaripiprazole (DHAr) are sensitive, but difficult to use in a hospital context. We aimed to develop a rapid LC-MS/MS method allowing reliable level measurement in the presence of co-administered drugs, withdrawing samples from 22 patients with acute agitation receiving 9.75 mg aripiprazole IM injection. METHOD We developed a sensitive and selective HPLC-MS/MS method to measure serum Ar and DHAr levels in a hospital laboratory, requiring minimal sample preparation and inferior sample volume compared to previous LC-MS/MS methods. Analytes were separated on a reversed-phase HPLC (run-time, 10 min). A triple quadrupole tandem mass spectrometer was used for quantitative analysis in positive mode by a multiple reaction monitoring. Samples were drawn 2, 4, 6, and 24h post-injection. RESULTS Calibration curves (2-1000 ng/mL for Ar and 3.5-500 ng/mL for DHAr) were linear, with mean correlation coefficient >0.9998. Within- and between-day precision and accuracy were within 10%. Mean recovery was 95.2 ± 4.5% for Ar and 97.6 ± 7.2% for DHAr. Ar and DHAr peaks were not affected by other co-administered psychotropic drugs. CONCLUSION Our method measured Ar and DHAr concentrations reliably, simply and rapidly without employing many reagents, as currently existing methods.

Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

Objectives. To review the role of Wnt pathways in the neurodevelopment of schizophrenia. Methods: Systematic PubMed search, using as keywords all the terms related to the Wnt pathways and crossing them with each of the following areas: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. Results: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. Conclusions: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data.

The Impact of Anxiety, Depression, and Suicidality on Quality of Life and Functional Status of Patients With Congestive Heart Failure and Hypertension: An Observational Cross-Sectional Study

OBJECTIVE Congestive heart failure (CHF) and hypertension are prevalent diseases with high mortality and morbidity rates. Depression and anxiety are frequently associated with cardiovascular diseases. This observational cross-sectional study assessed depression, anxiety, suicidality, and quality of life in 240 patients with CHF (with or without hypertension) or hypertension (without CHF). METHOD Subjects were evaluated between June 2005 and June 2007 using the Hamilton Anxiety Rating Scale (HARS), Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Medical Outcomes Study 36-item Short-Form Health Survey (both physical component score and mental component score), and Satisfaction With Life Scale (SWLS). Patients with CHF were assigned a New York Heart Association functional classification. RESULTS The CHF patients had higher scores on the depressive factor and the HARS and higher suicidality. Furthermore, they had lower scores on the physical component score, higher scores on the mental component score, and lower scores on the SWLS. Depressive symptom level was a significant predictor of lower physical health (P = .012), whereas anxiety was a significant predictor of satisfaction with life (P = .002). CHF compared to hypertension was a predictor of higher mental health as measured with the mental component score and lower satisfaction with life. Higher anxiety predicted lower satisfaction with life both in patients with CHF and with hypertension. CONCLUSIONS Anxiety and depressive symptoms and cardiovascular disease were frequently associated. Screening for anxiety and depression in cardiovascular patients may be crucial.

Intramuscular Aripiprazole in the Acute Management of Psychomotor Agitation

To assess acute efficacy and safety of 9.75 mg of intramuscular (IM) injections of the atypical antipsychiatric aripiprazole in patients with schizophrenia or bipolar disorder and acute agitation.

Risperidone-induced leukopenia: a case report and brief review of literature

A Caucasian, male, young adult with recurrent agitated depression and suicidal ideation received lithium and oral olanzapine. His white blood cell count was normal at that time. Due to unsatisfactory response, he received 4 mg/day risperidone. While symptoms improved, leukopenia emerged, specifically directed towards neutrophils. Upon risperidone discontinuation, white blood cell count returned to reference values within 1 week. As symptom control was satisfactory, we attempted no risperidone rechallenge. Accurate blood testing must accompany atypical antipsychotic drug administration since blood dyscrasias are always possible with these drugs.

Neurobiological Evidence for the Primacy of Mania Hypothesis

Background: Athanasios Koukopoulos proposed the primacy of mania hypothesis (PoM) in a 2006 book chapter and later, in two peer-reviewed papers with Nassir Ghaemi and other collaborators. This hypothesis supports that in bipolar disorder, mania leads to depression, while depression does not lead to mania. Objective: To identify evidence in literature that supports or falsifies this hypothesis. Method: We searched the medical literature (PubMed, Embase, PsycINFO, and the Cochrane Library) for peer-reviewed papers on the primacy of mania, the default mode function of the brain in normal people and in bipolar disorder patients, and on illusion superiority until 6 June, 2016. Papers resulting from searches were considered for appropriateness to our objective. We adopted the PRISMA method for our review. The search for consistency with PoM was filtered through the neurobiological results of superiority illusion studies. Results: Out of a grand total of 139 records, 59 were included in our analysis. Of these, 36 were of uncertain value as to the primacy of mania hypothesis, 22 favoured it, and 1 was contrary, but the latter pooled patients in their manic and depressive phases, so to invalidate possible conclusions about its consistency with regard to PoM. All considered studies were not focused on PoM or superiority illusion, hence most of their results were, as expected, unrelated to the circuitry involved in superiority illusion. A considerable amount of evidence is consistent with the hypothesis, although indirectly so. Limitations. Only few studies compared manic with depressive phases, with the majority including patients in euthymia. Conclusion: It is possible that humans have a natural tendency for elation/optimism and positive self-consideration, that are more akin to mania; the depressive state could be a consequence of frustrated or unsustainable mania. This would be consistent with PoM.

Hiccup with aripiprazole plus benzodiazepines resolving with pregabalin and/or benzodiazepine switch/discontinuation: four case reports.

To the Editors: H iccup lasting for more than 2 days is termed protracted and hiccup lasting for more than 2 months is termed intractable; hiccup is associated with high mortality. The neurochemistry associated with hiccup is unknown. However, it is believed that dopamine facilitates the hiccup, whereas γ-aminobutyric acid (GABA) reduces it through GABAB receptors but may increase it through GABAA receptors. 2 In fact, antiparkinsonian medication induces it, whereas dopamine receptor blockers and the GABAB agonist baclofen are used in its treatment. Alternative proposed treatments include the dihydropyridine L-type calcium channel blocker, nimodipine, and the α2δ subunit of voltage-gated calcium channels ligands gabapentin and pregabalin. Gabapentin and pregabalin are active on L-, N-, P-, and R-type calcium channels. Summarizing the previous data, D2 dopamine and GABAA receptor facilitation activates the hiccup reflex in combination with voltage-gated calcium ions, whereas GABAB receptor activation, dopamine D2 inhibition, and voltage-gated calcium channel blockade inhibit the reflex. Calcium ion channel inhibition is able to block hiccup; however, the mechanism is currently unknown. Interestingly, dopaminergic firing of ventral tegmental area dopamine neurons is supported by N-type channels, and both Nand P-type channel–mediated calcium ion influx facilitate somatodendritic and terminal dopamine release. In addition, GABAB receptors directly inhibit voltage-gated calcium ion channels, whereas GABAA receptor activation increases intracytosol calcium in astrocytes

Does the efficacy of asenapine in bipolar disorder increase in the presence of comorbidity with a substance use disorder? A naturalistic study

Background: Asenapine is a second-generation antipsychotic approved in Europe for treating moderate-to-severe manic episodes in adults affected by type I bipolar disorder (BD-I). We aimed to compare its efficacy in psychiatric inpatients with BD-I, with or without substance use disorder (SUD). Methods: We administered flexible asenapine doses ranging from 5–20 mg/day to 119 voluntarily hospitalized patients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) BD-I diagnosis, with or without SUD. Patients were assessed with clinician-rated questionnaires [i.e. Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Global Assessment of Functioning (GAF)]. Assessments were carried out at baseline (T0, prior to treatment), and 3 (T1), 7 (T2), 15 (T3), and 30 days (T4) after starting treatment for all clinical scales and at T0 and T4 for the GAF. Results: Patients improved on all scales (p < 0.001) across all timepoints, as shown both by paired-sample comparisons and by applying a repeated-measures, generalized linear model (GLM). Patients without comorbid SUD showed greater reductions in BPRS scores at T2 and T3, greater reduction in YMRS scores at T3, and lower HARS scores at all timepoints. HDRS scores did not differ between the two groups at any timepoint. However, the reduction in HARS scores in the comorbid group was stronger than in the BD-I only group, albeit not significantly. Side effects were few and mild-to-moderate. Conclusions: The open-label design and the relatively short observation period may expose to both type I and type II statistical errors (false positive and false negatives). Asenapine showed effectiveness and safety in hospitalized BD-I patients. Its effect was stronger in patients without comorbid SUD.

Lacosamide in bipolar disorder: A 30-day comparison to a retrospective control group treated with other antiepileptics: Lacosamide in bipolar disorder

Bipolar disorder (BD) is often treated with anticonvulsants. Lacosamide has not been tested in BD. We assessed its effects in a hospital setting in patients with BD without epilepsy.

Head-to-head comparison of 1-year aripiprazole long-acting injectable (LAI) versus paliperidone LAI in comorbid psychosis and substance use disorder: impact on clinical status, substance craving, and quality of life

Background To overcome nonadherence in patients with psychosis switch to long-acting injectable (LAI) antipsychotic formulations is adopted. Most oral versus LAI comparisons showed similar antipsychotic responses. Psychoses often overlap with substance use disorder (SUD). Head-to-head LAI comparisons have hitherto focused only on non-comorbid populations. Objective The objective of this study was to compare two LAIs, administered for 12 months, in initially hospitalized patients with psychosis comorbid with SUD in their clinical and quality of life (QoL) outcomes. Patients and methods Inpatients were recruited during 2016 and switched randomly to 400 mg intramuscular aripiprazole monohydrate (AM) (N=50) or to 100 mg intramuscular paliperidone palmitate (PP) once-monthly (N=51); patients were discharged and followed up for 12 months. Patients were rated at baseline and after 1 year through the Clinical Global Impression scale – severity (CGIs), substance craving intensity was rated through a visual analog scale for substance craving, and QoL through the World Health Organization (WHOQOL-BREF) scale. We addressed confounders with backward stepwise logistic regression and three-way analysis of variance. Results PP were older and had more cases of schizophrenia spectrum and less bipolar disorders than AM, but AM had a stronger craving for substances at baseline. Both LAIs were associated with significant improvements in all outcomes, with AM displaying stronger effect sizes than PP. The two groups did not differ on baseline WHOQOL-BREF scores in any domain, but at the 1-year follow-up, AM fared better on all domains. The two groups did not differ in final severity, but PP scored higher than AM in craving at the 1-year endpoint. Limitation: The CGIs is not a refined tool for severity and the substance craving may be subject to recall bias. Conclusion 1-year AM and PP was followed by improved clinical status and QoL and reduced substance craving in a population with psychosis and SUD comorbidity. AM, compared to PP, improved craving and QoL at the 1-year follow-up.