Alessio Fiorentini

Clinical pharmacokinetics of atypical antipsychotics : A critical review of the relationship between plasma concentrations and clinical response

In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients’ quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of Clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics.In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects.Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods.Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350–420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking.The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form.The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20–50 ng/mL has been found.There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial.Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100–400 ng/mL is proposed from non-systematic clinical experience.There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.

Patterns of clinical use of antipsychotics in hospitalized psychiatric patients

The ways of using antipsychotic drugs have greatly changed over the last 10 years. The aim of this study was to evaluate such changes in psychiatric patients admitted to the Psychiatric Department of Milans Ospedale Maggiore in 1989 (n=350), 1999 (n=718) and 2002 (n=628). The medical records of the hospitalized patients were evaluated by analyzing the anamnestic and clinical data with particular reference to age, gender, diagnosis and medication use. In 2002, atypical antipsychotics were more frequently prescribed as monotherapy upon discharge than typical antipsychotics (32.64% vs. 30.10%). Combinations of two or more antipsychotic drugs were prescribed upon discharge for 20.63% of the patients in 1989, 31.24% in 1999 and 23.09% in 2002. The combinations of one typical and one atypical drug increased from 4.04% in 1999 to 13.06% in 2002. The mean (+/-S.D.) daily antipsychotic drug dose (expressed in chlorpromazine equivalents) was significantly higher in 2002 than in 1999 and 1989. The results of this study confirm the trend to use combinations of one typical and one atypical antipsychotic, and higher doses.

Clinical outcome and tolerability of duloxetine in the treatment of major depressive disorder: A 12-week study with plasma levels

Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor that has been recently approved for the treatment of major depressive disorder (MDD). However, little is known about the relationship between DLX plasma levels and clinical response. The aims of this open-label study were 1) to assess clinical outcome and tolerability of DLX by means of clinician and patient assessments and 2) to evaluate the value of plasma DLX levels as predictors of clinical response and tolerability. This was a naturalistic, open-label study of 45 outpatients affected with MDD (16 men and 29 women), who received DLX at doses of 30—120 mg/day and were evaluated at baseline (T0) and after 2, 4 and 12 weeks (T1—3). The assessments included the Hamilton Rating Scales for Depression (HRSD) and Anxiety (HRSA), Clinical Global Impression-Severity (CGI-S), Beck’s Depression Inventory (BDI) and a mood visual analogue scale (VAS). Compared with T0, there were significant improvements in HRSD at T1, T2 and T3 (P < 0.001), in HRSA, CGI-S and the self-administered BDI at T2 and T3 (P < 0.001), and in the VAS scores shown at T3 (P = 0.01). DLX treatment was safe and well tolerated. Plasma DLX levels at T2 ranged from 5 to 135 ng/mL (mean ± SD = 53.56 ± 39.45) and correlated almost significantly with the DLX dose (r = 0.35; P = 0.069). There was a significant curvilinear quadratic relationship between the improvement of HRSA scores and plasma DLX levels (R2 = 0.27; P = 0.02). The incidence of anxiety or irritability was associated with the highest plasma levels. Our findings suggest that monitoring plasma DLX levels may be helpful in predicting better treatment responses and tolerability. The present data seem to suggest an optimal anxiolytic efficacy of DLX at intermediate plasma levels.

Is trazodone more effective than clomipramine in major depressed outpatients? A single-blind study with intravenous and oral administration

OBJECTIVE Some antidepressants, such as trazodone or clomipramine, can be administered intravenously in patients with major depressive disorder (MDD), with potential benefits compared to the standard oral treatment, but available data about their efficacy are limited. The present study was aimed to compare the effectiveness of trazodone and clomipramine (intravenous [i.v.] followed by oral administration). METHODS Some 42 patients with a diagnosis of MDD according to the DSM-5 were selected and treated with i.v. trazodone or clomipramine according to clinical judgment. The Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Montgomery-Åsberg Depression Rating Scale were administered at baseline, after 2 weeks, and after 6 weeks, as well as after 1 week of intravenous antidepressant administration. Raters were blinded to type of treatment. RESULTS No significant differences were found between treatment groups in terms of effectiveness at endpoint. Borderline statistical significance was found in terms of number of responders in favor of trazodone. In addition, patients treated with trazodone reported fewer total side effects than those treated with clomipramine. CONCLUSION Both i.v. trazodone and clomipramine are rapid and effective options for improving depressive symptoms, although trazodone appears to be tolerated better. Further studies with larger samples and double-blind conditions are warranted to confirm our results.

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.