The Switch From Paliperidone Long-Acting Injectable 1- to 3-Monthly: Clinical Pharmacokinetic Evaluation in Patients With Schizophrenia (Preliminary Data).

PURPOSE/BACKGROUND: The aim of the study was a preliminary evaluation of the maintenance of clinical efficacy and tolerability of paliperidone palmitate in patients with schizophrenia during the transition phase from 1-monthly paliperidone palmitate formulation (PP1M) to PP3M, with the evaluation of plasma levels of the drug. METHODS/PROCEDURES: A prospective observational study was conducted for 13 months involving 22 outpatients, aged 18 to 66 years and clinically stabilized. Patients were affected by schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. For each patient, clinical assessment, safety and tolerability, and drug plasma level determination were performed. Clinical efficacy was assessed by Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale, and Hamilton Rating Scale for Depression. During the first 4 months of the study, once-monthly paliperidone palmitate was administered, and then during the following 9 months, the 3-monthly formulation was administered. FINDINGS/RESULTS: The time course of the Brief Psychiatric Rating Scale total scores showed a statistically significant (P = 0.006) improvement from T0 to T8; Positive and Negative Symptom Scale scores showed a similar time course, with a statistically significant (P = 0.0016) reduction of the mean total score; Hamilton Rating Scale for Depression mean scores showed a statistically significant (P = 0.003) reduction with substantial maintenance of clinical stabilization of the patients. Only 1 patient dropped out after the first PP3M injection. IMPLICATIONS/CONCLUSIONS: Our preliminary data currently confirm the maintenance of clinical stability shifting from PP1M to PP3M.

Musical practice and BDNF plasma levels as a potential marker of synaptic plasticity: an instrument of rehabilitative processes.

BACKGROUND AND OBJECTIVES: The aim of the study was to investigate the influence of musical practice on brain plasticity. BDNF (brain-derived neurotrophic factor) is a neurotrophin involved in neuroplasticity and synaptic function. MATERIALS AND METHODS: We recruited 48 healthy subjects of equal age and sex (21 musicians and 27 non-musicians). All subjects were administered the AQ (Autism-Spectrum Questionnaire) and plasma levels (PLs) of BDNF, oxytocin (OT), and vasopressin (VP) were measured in the blood sample of every participant. RESULTS: The difference between BDNF PLs in the two groups was found to be statistically significant (t = - 2.214, p = 0.03). Furthermore, oxytocin (OT) PLs and musical practice were found to be independent positive predictors of BDNF PLs (p < 0.04). We also found a negative correlation between BDNF PLs and AD (attention to detail) sub-scale score of AQ throughout the whole sample. Assuming BDNF PLs to be a marker of synaptic plasticity, higher PLs could be associated with the activation of alternative neural pathways: a lower score in the "attention to detail" sub-scale could imply greater flexibility of higher cerebral functions among musicians. Further researches should be conducted to assess the rehabilitative usefulness of these findings among patients affected by psychiatric disorders.

Paliperidone LAI and Aripiprazole LAI Plasma Level Monitoring in the Prophylaxis of Bipolar Disorder Type I with Manic Predominance.

INTRODUCTION: The objective of this study was the evaluation of utility of plasma level monitoring in the clinical stabilizing efficacy and tolerability of paliperidone palmitate (PP) vs. aripiprazole monohydrate (AM) in bipolar disorder I (BD I) with manic predominance. METHODS: Fifty-six outpatients of both sexes, age ranging from 18 to 65 years, affected by BD I with manic predominance, orally treated and stabilized after acute episode for at least 2 weeks with paliperidone or aripiprazole (n=31, paliperidone; n=25, aripiprazole) underwent a prospective observational study of switching to the corresponding long-acting injection (LAI) on the basis of clinical evaluation. The efficacy and tolerability of the 2 treatments were assessed by BPRS, PANSS, HAMD21, and MRS rating scales and a check list every month for 12 months. Drug plasma levels determinations (PLs) were performed at the same times. RESULTS: A good clinical stability and tolerability of both drugs were reported. Lower mean PLs of PP showed a positive effect on depressive symptoms. AM PLs variability was associated with greater instability of manic symptoms whereas intermediate PLs seem to have more influence on depressive symptomatology. DISCUSSION: PLs drug monitoring has been proven to be useful, and further investigations to identify optimal therapeutic ranges for LAI formulations are needed.

Paliperidone Long-Acting Plasma Level Monitoring and a New Method of Evaluation of Clinical Stability.

The second generation long-acting antipsychotics can be a pharmacologic strategy, both in the early phase of illness and in the case of low compliance. The aim of the study was to evaluate the clinical efficacy and tolerability of one monthly injection of paliperidone palmitate (PP1M), paliperidone plasma levels (PLs), and the clinical outcome. 21 outpatients, affected by Schizophrenia or Schizoaffective Disorder, were recruited. PP1M started with 150 mg on day 1 and 100 mg on day 8. Following patients were given a dosage ranging from 50 mg to 150 mg every 28 days. At baseline, and then monthly, patients were clinically evaluated. BPRS and PANSS total score showed a statistically significant decrease from T2 (after 2 months) to T12 (after 12 months). The PLs steady-state was approximatively reached after the fifth injection (T4). All the patients showed a clinical stabilization: BPRS and PANSS scores showed a significant improvement from T2. PLs data seems to suggest the initial possibility of an oral supplementation, although clinical evaluation demonstrated no relapse during the study.

Duloxetine in elderly major depression disorder: effectiveness and drug plasma level evaluation.

OBJECTIVE: The aim of this open-label naturalistic study was to assess clinical outcomes and the predictive value of duloxetine plasma levels in major depressive disorder in the elderly. METHODS: This naturalistic, open-label design involved 35 outpatients aged between 65 and 87 years. Duloxetine plasma levels were collected in 24 patients after the first month. Patients were evaluated using 21-item Hamilton Rating Scales for Depression, Hamilton Rating Scales for Anxiety, the Clinical Global Impression Severity, Mini Mental State Examination, Cumulative Illness Rating Scale, Barthel Index and Beck's Depression Inventory. RESULTS: Duloxetine plasma levels at T2 ranged from 4.9 to 201.9 ng/mL without a significant correlation between duloxetine dose and plasma levels. A significant improvement in mean 21-item Hamilton Rating Scales for Depression total scores at T2,T3, T4, T9 and T12 and a progressive significantly decrease of the mean Hamilton Rating Scales for Anxiety scores from T3 to T12 were observed. CONCLUSIONS: The levels of duloxetine in plasma do not correlate with a greater clinical improvement, indeed appear to adversely affect the improvement of the Beck Depression Inventory and Hamilton Rating Scales for Anxiety. This could be explained by an increase in side effects that may aggravate the discomfort felt by the patient. Copyright © 2016 John Wiley & Sons, Ltd.

Aripiprazole in acute mania and long-term treatment of bipolar disorder: a critical review by an Italian working group.

Bipolar disorder (BD) is a chronic illness that is characterized by recurrent episodes of mania, depression or mixed symptoms. BD has a prevalence of approximately 2-4% in the general population and is associated with a substantial burden in terms of morbidity and mortality. Mania is one of the most difficult to treat manifestations of BD and antipsychotic drugs play a major therapeutic role in this respect. Acting mainly at dopamine receptors, first-generation antipsychotics are effective in controlling symptoms of BD; however, these drugs cause troublesome extrapyramidal symptoms (EPS) and hyperprolactinaemia. The more recently developed second-generation antipsychotics, which act at other receptors, provide a broader spectrum of clinical efficacy and have a more favourable tolerability profile than first-generation antipsychotics. Some second-generation antipsychotics are, however, associated with adverse effects such as weight gain and metabolic disorders, which may be cause for concern. Aripiprazole, a recently introduced second-generation antipsychotic, has a unique receptor-binding profile and mechanism of action, which are thought to account for its low propensity for weight gain, metabolic disturbances and sedation. Aripiprazole is approved in the US and in Europe for the acute management and maintenance of manic and mixed episodes associated with bipolar I disorder. In both the acute and long-term maintenance settings, clinical trials have shown aripiprazole to be clinically effective in terms of response rates, remission rates and prevention of relapse. The lack of a sedative effect does not affect the efficacy of aripiprazole in controlling mania and agitation. With both short- and long-term aripiprazole treatment, adverse event rates were similar to placebo and significantly lower than seen with comparators; one exception to this is the occurrence of EPS, which was observed more frequently in aripiprazole recipients than in patients receiving placebo, but less frequently than in patients treated with haloperidol. Aripiprazole is likely to promote treatment adherence because of its favourable tolerability profile, but more specifically focused studies are required to confirm this hypothesis. The efficacy and favourable metabolic profile of aripiprazole make it a good option in the management of acute mania and maintenance treatment, especially in an outpatient setting. Thus, aripiprazole provides clinicians with a valuable additional therapeutic option for BD. Cognizant of the lack of standardized strategies for aripiprazole dosing, switching, and prevention and management of adverse effects, an expert consensus meeting was held in Italy with the aim of producing guidelines for the use of aripiprazole in acute and long-term management of BD mania. The resulting dosage, administration and switching recommendations outlined in this report are based on empirical results from well designed aripiprazole clinical trials and clinical experience, and are in accord with the manufacturer's prescribing information. However, careful evaluation of the individual patient and a thorough risk/benefit assessment should be made prior to initiating any treatment plan.

Symptom dimensions as predictors of clinical outcome, duration of hospitalization, and aggressive behaviours in acutely hospitalized patients with psychotic exacerbation.

In the present study we extract clusters of symptoms in acute hospitalized psychotic patients during a re-exacerbation phase, using factor analysis of BPRS-E. We aim to investigate the relative contribution of each symptom dimension in predicting the severity of symptoms at discharge, the length of acute hospitalization, and the occurrence of aggressive behaviours during acute hospitalization. The data are drawn from a prospective, naturalistic, observational study of 183 patients with Psychotic Disorders consecutively admitted to a psychiatric ward, during a re-exacerbation phase. General symptomatology has been measured through BPRS-E at admission and at discharge. Statistical analyses include principal component analysis and multiple linear regression.We found symptoms of acute psychosis disorder to cluster together in four distinct domains, labelled "Excitement/Activation", "Positive symptoms", and "Negative symptoms", and "Depression/Anxiety". Excitement/activation was the dimension most associated with occurrence of aggressive behaviours and severity of psychopathological symptoms at discharge. The negative symptoms dimension, also, predicted the severity of symptoms at discharge. Positive and negative symptoms dimensions were both predictors of duration of hospitalization. The depressive dimension was significantly associated only to self-aggression. These data indicate that during acute hospitalization due to re-exacerbation of psychosis each symptom dimension has a specific impact on distinct measures of outcome.

Correction to: Clinical Pharmacokinetics of Atypical Antipsychotics: An Update.

The pharmacokinetics of CRP was tested in small short-term studies in both healthy volunteers and in subjects with schizophrenia, with similar results [242].

Clinical Pharmacokinetics of Atypical Antipsychotics: An Update.

Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally effective blood concentrations. The rationale for using therapeutic drug monitoring in relation to second-generation antipsychotics is still being discussed at least with regard to the real clinical utility, but there is evidence that it can improve efficacy, especially when patients do not respond or develop side effects using therapeutic doses. Furthermore, drug plasma concentration determinations can be of some utility in medico-legal problems. This review concentrates on the clinical pharmacokinetic data related to clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, sertindole, asenapine, iloperidone, lurasidone, brexpiprazole and cariprazine and briefly considers the main aspects of their pharmacodynamics. Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine, amisulpride, asenapine, iloperidone and lurasidone provide only limited information and there is no direct evidence concerning ziprasidone, aripiprazole, sertindole, brexpiprazole and cariprazine: the few reported investigations need to be confirmed and extended.

A single-blind, randomized comparison of olanzapine at a starting dose of 5 mg versus 20 mg in acute schizophrenia.

Acute psychotic episodes represent critical situations during the course of schizophrenia. Olanzapine (OLZ), a second-generation antipsychotic, is efficacious in acute settings at dosages of 5 to 20 mg/d, and it can be considered a first-line treatment for patients with an acute episode of schizophrenia. The aim of this study was to evaluate the efficacy and tolerability of OLZ at a starting dose of 5 mg versus 20 mg in acute schizophrenic patients and to compare titration versus nontitration.Fifty-one schizophrenic inpatients were randomly assigned to receive OLZ at 5 mg/d (26 patients, group 1) or 20 mg/d (25 patients, group 2) as a starting dosage during an exacerbation phase. In group 1, the OLZ dosage was increased to a mean dosage of 10.55 (+/- 4.00) mg/d. Group 2 received OLZ at a fixed dose of 20 mg throughout the hospitalization period. Olanzapine was significantly and clinically effective on Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale, PANSS positive symptoms, and Hamilton Rating Scale for Depression in both groups. There were no significant differences between groups 1 and 2 in the percent improvement in BPRS, Positive and Negative Syndrome Scale, PANSS positive symptoms, PANSS negative symptoms, or Hamilton Rating Scale for Depression; but group 2 was significantly superior in the mean percent improvement in the BPRS items of anxiety (P < 0.001) and suspiciousness (P < 0.05). In conclusion, the higher doses evidence more efficacy on anxiety and suspiciousness, so it seems to be useful to begin therapy with a full dose of the drug to obtain the maximum effect without any significant side effects.

Cabergoline can induce mania with psychotic features in bipolar I disorder: a case report.

Up to date, only a small evidence of psychosis induced by cabergoline is available in literature. Herein, the case of a 34-year-old bipolar patient treated with cabergoline has been described. Cabergoline is generally a safe and effective method of reducing prolactin levels and it may be associated with psychiatric side effects, including psychotic features.

Parasuicide and drug self-poisoning: analysis of the epidemiological and clinical variables of the patients admitted to the Poisoning Treatment Centre (CAV), Niguarda General Hospital, Milan.

Epidemiological knowledge of parasuicides and drug self-poisoning is still limited by a lack of data. A number of preliminary studies, which require further analysis, evidenced that parasuicidal acts occur more often among females, that the peak rate is generally recorded between the ages of 15 and 34 years and psychotropic medications seems to be the most frequently used. The aim of this study was to describe the demographic and clinical variables of a sample of subjects admitted to the Posisoning Treatment Centre (CAV), Niguarda General Hospital, Milan, following drug self-poisoning. Furthermore, this study is aimed to identify the risk factors associated to parasuicidal gestures, with special care for the used drugs, the presence of psychiatric or organic disorders, alcoholism and drug addiction.The study included the 201 patients attending the CAV in 1999 and 2000 who satisfied the criteria of self-poisoning attempts: 106 cases in 1999 and 95 in 2000.The sample had a prevalence of females (64%). The peak rates of parasuicides from drug self-poisoning were reached between 21 and 30 years among the females, and 31 and 40 years among the males. 81.6% of the patients used one or more psychoactive drugs, the most frequent being the benzodiazepines (58.7%), classic neuroleptics (16.9%) and new-generation antidepressants (SSRIs, SNRIs, NARIs) (12.9%). The prevalence of mood disorders was higher among females (64% vs 42%), whereas schizophrenia was more frequently diagnosed in males (22% vs 10%). 61% (33%) had a history of previous attempted suicides. The presence of clinically relevant organic diseases was observed in 24.9% of the sample.

Pharmacokinetic evaluation of agomelatine for the treatment of generalised anxiety disorder.

INTRODUCTION: Preliminary data indicate agomelatine as a promising molecule for both acute and long-term treatment of generalised anxiety disorder (GAD). AREAS COVERED: The present review illustrates the pharmacokinetic properties of agomelatine and their implications for the management of GAD patients. A search of the main database sources (Medline, Isi Web of Knowledge and Medscape) was performed in order to obtain a complete and balanced evaluation of agomelatine pharmacokinetics for the treatment of GAD. The word 'agomelatine' was associated with 'pharmacokinetics', 'GAD', 'anxiety' and 'tolerability'. No restriction criteria were established in relation to methodology or year of publication. Only English-language articles were included. EXPERT OPINION: Short half-life and 1-day administration make agomelatine an interesting molecule for GAD treatment. However, potential interactions with a number of compounds necessitate caution when prescribing and using agomelatine in patients with psychiatric (e.g., alcohol abuse) or medical comorbidities. Further data are necessary to define a precise risk/benefit ratio in special populations such as elderly patients suffering from GAD.

Pharmacokinetics of antidepressants in patients with hepatic impairment.

Appropriate use of antidepressant in patients with hepatic impairment requires careful consideration of how the hepatic illness may affect pharmacokinetics. This review aims to analyze pharmacokinetic profile, plasma level variations so as the metabolism of several antidepressants relating to their use in patients with an hepatic impairment. Due to the lack of data regarding hepatic impairment itself, the review is focused mainly on studies investigating pharmacokinetics in hepatic cirrhosis or alcohol-related conditions. More data on reduced hepatic metabolism can be extrapolated by drug studies conducted in elderly populations. Dose adjustment of antidepressants in these patients is important as most of these drugs are predominantly metabolized by the liver and many of them are associated with dose-dependent adverse reactions. As no surrogate parameter is available to predict hepatic metabolism of drugs, dose adjustment according to pharmacokinetic properties of the drugs is proposed. There is a need for a more balanced assessment of the benefits and risks associated with antidepressants use in patients with hepatic impairment, particularly considering pharmacokinetic profile of the drugs to ensure that patients, who would truly benefit from these agents, are not denied appropriate treatment. In conclusion, kinetic studies for centrally acting drugs including antidepressants with predominant hepatic metabolism should be carried out in patients with liver disease to allow precise dose recommendations for enhanced patient safety.

Arterial hypertension and posterior reversible cerebral edema syndrome induced by risperidone.

Posterior reversible cerebral edema syndrome is a generally reversible neurologic condition that is diagnosed based on distinctive clinical and radiologic findings. The condition, which is mostly associated with severe arterial hypertension, has also been reported to be induced by several medications. We made the diagnosis of hypertension with posterior reversible cerebral edema syndrome in a lean 12-year-old girl treated with the second-generation antipsychotic risperidone. We applied the Naranjo Adverse Drug Reaction Probability Scale and the World Health Organization-Uppsala Monitoring Centre system for causality assessment to the present case. Both scales indicated that a relationship to risperidone was likely. Second-generation antipsychotic agents may occasionally induce an increase in blood pressure even in the absence of overweight. Given this possibility, we recommend routine monitoring of blood pressure during therapy with these agents.

Understanding the pharmacokinetics of anxiolytic drugs.

INTRODUCTION: Anxiety disorders are considered the most common mental disorders and they can increase the risk for comorbid mood and substance use disorders, significantly contributing to the global burden of disease. For this reason, anxiolytics are the most prescribed psychoactive drugs, particularly in the Western world. AREAS COVERED: This review aims to analyze pharmacokinetic profile, plasma level variations so as the metabolism, interactions and possible relation to clinical effect of several drugs which are used primarily as anxiolytics. The drugs analyzed include benzodiazepines, anticonvulsants (pregabalin, gabapentin), buspirone, ß-blockers and antihistamines (hydroxyzine). Regarding the most frequently used anxiolytic benzodiazepines, data on alprazolam, bromazepam, chlordesmethyldiazepam, chlordiazepoxide, clotiazepam, diazepam, etizolam, lorazepam, oxazepam, prazepam and clonazepam have been detailed. EXPERT OPINION: There is a need for a more balanced assessment of the benefits and risks associated with benzodiazepine use, particularly considering pharmacokinetic profile of the drugs to ensure that patients, who would truly benefit from these agents, are not denied appropriate treatment. An optimal pharmacological approach involving an integrative pharmacokinetic and pharmacodynamic optimization strategy would ensure better treatment and personalization of anxiety disorders. So it would be desirable for the development of new anxiolytic drug(s) that are more selective, fast acting and free from the unwanted effects associated with the traditional benzodiazepines as tolerance or dependence.

[Psychiatric features before and after intervention: a study of patients affected by severe obesity undergoing adjustable gastric banding]. / Tratti psichiatrici pre- e post-intervento: studio di un campione di pazienti affetti da grave obesità sottoposti a bendaggio gastrico regolabile.

AIM: This study identifies psychological features and the evolution of psychiatric symptoms in a group of patients affected by obesity, who underwent adjustable gastric banding. MATERIALS AND METHODS: In this group, other than clinical visit, test SCL-90 is made in preoperative time. In postoperative SCL-90, TAS and BES were carried out. Patients evaluated before and after bariatric surgery were 220 and 115, respectively. SCL-90 test made before bariatric surgery showed high values (>0.7) for cluster related to somatization, interpersonal sensitivity, paranoid ideation, depression and obsessive compulsive disorder. DISCUSSION: Depression symptoms were more important in patients undergoing endogastric balloon placement (mean value of 0.9). Anxious symptoms showed a mean value of 0.73 in patients undergoing endogastric balloon placement as compared to a mean value of 0.52 in patients undergoing gastric banding. CONCLUSIONS: Our findings show that in patients undergoing bariatric surgery, depressive symptoms are more common preoperatively and normalize at follow-up. This confirms that a possible cause of depression is obesity. The present study also shows that anxious symptoms are lower in obese patients.