Silvia Paletta

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, β-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.

Clinical pharmacology of atypical antipsychotics: an update

This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que¬tiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects.

Effect of quetiapine and norquetiapine on anxiety and depression in major psychoses using a pharmacokinetic approach: A prospective observational study

AbstractBackground: Quetiapine apparently differs from other antipsychotic drugs in terms of its antidepressant activity and efficacy in bipolar depression. The mechanism of this activity is unknown although it may be mediated by its metabolite N-desalkylquetiapine (norquetiapine). Objective: The aim of the study was to analyse the relationships between quetiapine and norquetiapine plasma concentrations and clinical improvement in depressive and anxious symptoms. Methods: This was a prospective observational study. Recruited patients were evaluated during a clinical post-acute phase. Patients were recruited from patients hospitalized in the Psychiatric Department of Ospedale Maggiore Policlinico of Milan, Italy. After discharge they were followed-up as outpatients. The study involved 41 outpatients (23 males, 18 females; age >18 years) diagnosed as affected by schizophrenia (17 patients), borderline personality disorder (eight patients) or bipolar depression (16 patients) on the basis of the Diagnostic and Statistical Manual of Mental Disorders, fourth text revision (DSM-IV-TR) criteria. Patients were prescribed 50–800 mg of quetiapine (Seroquel®). Patients were evaluated after discharge from the psychiatric department (baseline, T0), after 15 days (T1) and after 3 months (T2) using the Brief Psychiatry Rating Scale (BPRS) with particular reference to the dimensions of depression (items 5, 9 and 13) and anxiety (items 1, 2 and 6). Plasma quetiapine and norquetiapine concentrations were determined by means of high-performance liquid chromatography at T2. Results: There was a significant improvement in the mean BPRS total score, as well as in the dimensions of anxiety and depression. The bipolar patients only showed a significant curvilinear relationship described by a second-order polynomial model between the plasma norquetiapine/quetiapine concentration ratio and the improvement in depression at T2. There was a significant negative linear correlation between the norquetiapine/quetiapine ratio and anxiety in all of the patients. Conclusion: The results of this study confirm the efficacy of quetiapine on both anxious and depressive symptoms. Norquetiapine has a specific effect on anxiety and depressive symptoms, showing a correlation between plasma concentrations and clinical efficacy only in patients with bipolar depression.

Clinical and neuropsychological correlates of major depression following post-traumatic brain injury, a prospective study.

OBJECTIVES Major depression disorder (MDD) is the most frequent psychiatric complication after traumatic brain injury (TBI), with a prevalence of 14-77%. The aim of this study was to analyse the psychiatric sequelae of TBI, and to identify the neuropsychological and psychopathological correlates of post-TBI MDD in order to highlight their differences from those of primary MDD. METHODS This was a longitudinal, prospective, case-control study. Sixteen patients with closed brain injury, and a lesion revealed by computed tomography (CT), were recruited and were evaluated one (T1), three (T3) and six (T6) months after discharge from Neurosurgery Department; the controls were six patients with MDD. The psychiatric symptoms were evaluated using brief psychiatric rating scale (BPRS), Hamilton depression rating scale (HRSD), Beck depression inventory scale (BDI), Hamilton anxiety rating scale (HRSA), global assessment of functioning (GAF) and instrumental activity of daily living (IADL). Neuropsychological profiles were assessed by using neuropsychological tests, focused on memory and frontal-executive functioning. RESULTS At T1, MDD was observed in 10 cases (62.5%), a manic episode in 12.5%, and post-traumatic stress disorder in 6.5%. At T3 and T6, MDD was diagnosed in, respectively, eight (50%) and six cases (37.5%). Post TBI MDD had less severe depressive symptoms, showed greater social isolation and hostility and more cognitive deficits in comparison with the control group. CONCLUSIONS MDD is a frequent TBI complication. Patients with post-TBI MDD have a specific psychopathological profile characterised by a less severe depressive symptomatology and a neuropsychological pattern that is significantly associated with greater deficits in cognitive functions than those with primary MDD.

Suicide attempts in schizophrenic patients: Clinical variables

INTRODUCTION Schizophrenia is associated with a significant risk of suicide: 40-50% of schizophrenic patients report suicidal ideation at some point in their lives, and 4-13% eventually commit suicide. In order to be able to predict and prevent suicide in schizophrenic patients, it is necessary to investigate and characterise suicide victims who meet the criteria for psychotic disorders and risk factors. METHODS The aim of this retrospective study was to verify the associations between suicide attempts (SAs) and the demographic and clinical variables of 106 patients who met the DSM-IV-TR criteria for schizophrenia. The patients were divided into two groups on the basis of the presence/absence of lifetime suicide attempts, and their main demographic and clinical characteristics were analysed and compared. RESULTS The patients with a history of SAs frequently had a duration of untreated psychosis (DUP) of ≥1 year (chi-squared test=9.984, df=1, p=0.0016). They also showed significant associations with the presence of a depressive dimension (chi-squared test=4.439, df=1, p=0.0351), hospitalisations before SAs (chi-squared test=25.515, df=1, p <0.001), and a family history of psychiatric disorders (chi-squared test=12.668, df=2, p=0.0018) or suicidal behaviours (chi-squared test=18.241, df=2, p=0.0001). Finally, they were more frequently prescribed typical antipsychotic agents. CONCLUSIONS The severity of psychiatric symptoms indicates a high risk of suicide in schizophrenic patients. Further prospective studies of larger samples should investigate the role of early interventions and atypical antipsychotic treatment in reducing the risk.

Aggression and psychopharmacological treatments in major psychosis and personality disorders during hospitalisation.

BACKGROUND A number of large-scale studies have shown that there is a relationship between many psychiatric disorders and aggression or violence. As no medication is currently approved for the treatment of aggression, pharmacotherapy (often involving drug combinations) is used on a trial-and-error basis with various degrees of response. METHOD The study involved 244 in-patients aged 19-83 years (mean 41.9 ± 11.3 SD). The Modified Overt Aggression Scale (MOAS) was used to assess any aggressive or violent behaviors occurring in the week before admission and upon discharge. Psychopathology was assessed using the Brief Psychiatric Rating Scales (BPRS). RESULTS All of the patients showed a significant improvement (p<0.001) in mean weighted total MOAS scores at the end of the study, with no significant differences between the various drugs or combination therapies. The patients who received combination treatments including antidepressants showed a worsening in the weighted total MOAS score (18.46% ± 114.31% SD); the patients who did not receive antidepressants had an improvement (13.61% ± 257.36% SD) (p=0.0069). CONCLUSIONS Multivariate testing of the variables age, gender, substance/alcohol abuse, the duration of hospitalisation, the administration of mood stabilisers, and the use of typical or atipical antipsychotics showed that the severity of the psychopathological picture correlated significantly with the presence of violence, whereas the effect of combined antidepressant treatment on violent behavior was only relative.

Paliperidone for the treatment of schizophrenia and schizoaffective disorders - a drug safety evaluation

ABSTRACT Introduction: Paliperidone, the major active metabolite of risperidone, is a second-generation antipsychotic that has been developed as an extended-release (ER) oral formulation and a long-acting injectable paliperidone palmitate (PP) formulation. Paliperidone has demonstrated efficacy in the reduction of acute schizophrenia symptoms and clinical benefits were maintained also in the long-term treatments. Paliperidone ER and PP are generally well tolerated with a predictable adverse event profile. Areas covered: Data from studies evaluating safety and tolerability in the acute and maintenance treatment of schizophrenia with paliperidone are reviewed. The reported treatment-emergent adverse events of these formulations are discussed. Expert opinion: In the treatment of schizophrenia and schizoaffective disorders the safety profile has a central role because it can enhance patient compliance. In fact treatment-emergent adverse events are one of the main causes of discontinuation in these patients. In particular the main limitation in the administration of paliperidone could be represented by the onset of hyperprolactinemia (especially in women) and of mild parkinsonism. Paliperidone has a high impact on current long-term drug strategies, especially given the new 3 month long-acting injectable formulation of PP.

long-acting olanzapine in maintenance therapy of schizophrenia: A study with plasma levels

Abstract Introduction. This prospective study was performed to evaluate clinical efficacy and tolerability of olanzapine long-acting injection (OLZ-LAI) and the relation between OLZ plasma level (PL) and the clinical outcome in maintenance therapy of schizophrenia. Material and methods. Twenty-five chronic schizophrenic outpatients with age ranging from 18 to 65 years were included in this 9-month study. Patients were given a dosage of either 210 or 300 or 405 mg of OLZ-LAI every 28 days. Patients were evaluated at baseline and every four weeks by Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Symptom Scale (PANSS); at the same time, PL of OLZ was determined. The metabolic profile (aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein, low-density lipoprotein, total cholesterol, and glucose levels) was analyzed every two months. Results. BPRS and total PANSS showed a statistically significant improvement from T2 with a clinical stabilization of psychopathological picture. PL ranged from 4.0 to 78.9 ng/ml (mean 20.59 ng/ml ± 14.66 standard deviation). The coefficient of variation of PLs was related to clinical stabilization. No post-injection delirium sedation syndrome occurred. Conclusions. Our data reveal the efficacy of OLZ-LAI in maintenance treatment of schizophrenia at lower dosages also in comparison with that of oral therapy. OLZ-LAI seems to be useful for guaranteeing constant PL of the drug. A lesser variation of PL was the most predictable factor associated with maintenance of clinical benefit.

Effect of N-Desalkylquetiapine/Quetiapine Plasma Level Ratio on Anxiety and Depression in Bipolar Disoder: A Prospective Observational Study

BACKGROUND The aim of this study was to analyze the relationships between quetiapine and N-desalkylquetiapine plasma levels and clinical improvement, particularly, in regard to depressive and anxious symptoms and to hostility. METHODS This was a prospective observational study that involved 37 outpatients diagnosed as having bipolar disorder I or II. All the patients were observed during a clinical acute and postacute phase. Patients were prescribed 50-800 mg of quetiapine. Patients were evaluated at baseline, after 15 days and after 3 months using the Brief Psychiatry Rating Scale with particular reference to the dimensions of depression, anxiety, and hostility. The plasma concentrations of quetiapine and N-desalkylquetiapine were determined after 3 months using blood samples taken at steady state. RESULTS There was a significant relationship between the N-desalkylquetiapine/quetiapine ratio and the improvement in the depression dimension, and there was not a significant relationship between the N-desalkylquetiapine/quetiapine ratio and anxiety and hostility improvement. Quetiapine treatment was well tolerated, and there were no extrapyramidal, anticholinergic, or other side effects to note. There was no relationship between plasma quetiapine or N-desalkylquetiapine concentrations and side effects. CONCLUSIONS Our findings confirm the efficacy of quetiapine on depressive symptoms, and the available data support that quetiapines antidepressant activity is mediated by the active metabolite norquetiapine, and it exemplifies the case of an active metabolite that can make a drug like quetiapine originally introduced as an antipsychotic a useful antidepressant agent.

Gray matter volumes may predict the clinical response to paliperidone palmitate long-acting in acute psychosis: A pilot longitudinal neuroimaging study

In schizophrenia, paliperidone palmitate (PP) long acting injectable (LAI) has been reported to sustain plasma concentrations and improve clinical symptoms. Moreover, it has also been demonstrated the important role of total gray matter (GM) volumes in predicting the clinical outcome. However, no studies investigating the association between PP-LAI treatment and brain morphometry has been published so far. Therefore, the main aim of our 24 weeks prospective observational exploratory study was to investigate the relation between brain anatomy and clinical outcome in seven patients with acute psychosis treated with PP-LAI. At baseline and every month (from T0 to T6) patients were clinically evaluated with the Brief Psychiatric Rating Scale (BPRS). 3T Magnetic Resonance Imaging at baseline was acquired and total GM and intracranial volumes were extracted to explore their predictive values on BPRS scores. After 24 weeks of treatment with PP-LAI, patients showed statistically significant improvements in BPRS scores. Moreover, subjects with higher total GM volumes had a significantly higher BPRS improvement at 24 weeks compared to patients with lower total GM volumes. Our findings confirm the effectiveness of PP-LAI in treating acute psychosis and suggest that greater GM volumes predict drug response, potentially supporting a favorable prognosis.