Lucia S. Volonteri

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.

Substance-Induced Psychoses: A Critical Review of the Literature

Substances with psychotomimetic properties such as cocaine, amphetamines, hallucinogens and cannabis are widespread, and their use or abuse can provoke psychotic reactions resembling a primary psychotic disease. The recent escalating use of methamphetamine throughout the world and its association with psychotic symptoms in regular users has fuelled concerns. The use of cannabis and cocaine by young people has considerably increased over recent years, and age at first use has dramatically decreased. There is some evidence that cannabis is now on the market in a more potent form than in previous decades. Furthermore, a large number of studies have reported a link between adolescent cannabis use and the development of stable psychosis in early adulthood. The situation is further complicated by the high rates of concomitant substance use by subjects with a psychotic illness which, especially in young users with an early-phase psychotic disorder, can make diagnosis difficult. This paper reviews the literature concerning the properties of psychotogenic substances and the psychotic symptoms they can give rise to, and discusses the association between substance abuse and psychosis with particular emphasis on the differential diagnosis of a primary and substance-induced psychotic disorder. The findings of this review indicate that psychosis due to substance abuse is commonly observed in clinical practice. The propensity to develop psychosis seems to be a function of the severity of use and dependence. From a phenomenological point of view, it is possible to identify some elements that may help clinicians involved in differential diagnoses between primary and substance-induced psychoses. There remains a striking paucity of information on the outcomes, treatments, and best practices of substance-induced psychotic episodes.

Predictors of clinical outcome in schizophrenic patients responding to clozapine.

Many of the patients who respond better to clozapine (CLZ) than to typical antipsychotics still have residual psychopathology, but CLZ drug resistance data are lacking. The aim of this study was to evaluate the possible predictive factors of a clinical response to CLZ in a group of 20 schizophrenic patients (DSM-IV: 13 males and 7 females with a mean age of 35.5 years ± 7.1 SD) resistant to typical antipsychotics but CLZ responders as assessed by the Brief Psychiatric Rating Scale (BPRS) (>20% improvement). After a 1-week washout period, CLZ was started at a dose of 25 mg/d, which was increased by the third week up to a maximum of 600 mg/d (mean 365.00 ± 129.88 mg/d SD) and remained unchanged until the end of the study (week 8). The patients showed a significant improvement in the mean scores of the rating scales for positive (SAPS) and negative symptoms of schizophrenia (Scale for the Assessment of Negative Symptoms, SANS) (P < 0.003, P < 0.02). All of the patients included in the study were BPRS responders; 65% were also SAPS and 75% SANS responders (>20% improvement). The improvement in the SANS score was significantly greater among the female patients (P < 0.05). The SAPS and SANS responders had a significantly higher mean metabolic ratio [MR = (NCLZ/CLZ)] than the nonresponders (P < 0.01), and the percentage of improvement significantly correlated with the increase in MR. This finding suggests that the individual pharmacogenetics indicated by metabolic capacity may be related to clinical response. All of the patients showed a reduction in white blood cell counts, but this was significantly less in the SANS responders than the SANS nonresponders (P = 0.047). The SAPS responders had significantly lower neutrophil counts than the nonresponders (P = 0.03). Our results seem to suggest the importance of pharmacodynamic, constitutional, and genetic data over strict pharmacokinetics in determining the clinical response to CLZ.

Clinical outcome and tolerability of sertraline in major depression: A study with plasma levels

Sertraline (SRT) has been shown to be an effective antidepressant in extensive clinical trial programs but data on plasma concentrations regarding clinical outcome and tolerability are lacking. Twenty-one out-patients of both sexes, with mean age of 50.23 years (S.D. = 17.37), affected by major depressive disorder, recurrent (Diagnostic and Statistical Manual of Mental Disorder--IV, DSM-IV), were treated with 25-150 mg of SRT once a day (mean=66.26 mg, S.D.=30.50) for 30 days. Clinical evaluation was assessed at baseline (T0), after 15 days (T15), and then after 30 days (T30). Plasma samples for SRT level determination were collected at T30. Brief Psychiatric Rating Scale (BPRS), Hamilton Rating Scale for Depression (HRS-D), and Hamilton Rating Scale for Anxiety (HRS-A) showed a significant improvement during the study (P<.01 vs. T0). The most commonly reported side effects were nausea (19%), cephalalgia (9.5%), dry mouth (9.5%), decreased libido (9.5%), tremor (4.7%), and tachycardia (4.7%). SRT plasma levels ranged from 2.82 to 112.20 ng/ml (mean=40.42 ng/ml, S.D.=26.93). No correlation between SRT plasma levels and clinical improvement or side effects were observed. Drug plasma level determination does not seem be strictly necessary from a clinical point of view but further research seems advisable in patients at risk like elderly and during long-term studies.

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.

Nutritional management of anorexic patients with and without fluoxetine: 1-year follow-up

This study evaluated the efficacy of nutritional management with and without fluoxetine (FLX) in anorexia nervosa diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Twenty-one patients, with a mean body mass index (BMI) of 15.21+/-2.33 kg/m(2), were treated with nutritional management and FLX at a mean dosage of 30.00+/-9.35 mg (pharmacological group); seventy-four patients, with a mean BMI of 14.24+/-2.16 kg/m(2), were treated only with nutritional management (nutritional group). Clinical evaluation was carried out under single-blind conditions at basal time and after 3, 6, and 12 months by a structured clinical interview, the Eating Disorder Interview based on Longitudinal Interval Follow-Up Evaluation (EDI-LIFE) and using a self-reported questionnaire, the Eating Disorder Inventory (EDI). BMI significantly increased in both the two treatment groups. In addition, the increase shown by the pharmacological group appeared near the beginning of treatment (i.e., at T1) and it was significantly higher than the increase shown by the nutritional group. Physical exercise showed a significant decrease in the pharmacological treatment group. On the other hand, fear of fatness and the scores of the subscales of the EDI significantly decreased in the nutritional treatment group. In terms of weight, the pharmacological group presented the higher amount of therapeutic success.

Predictive Value of Amino Acids in the Treatment of Major Depression with Fluvoxamine

Sixteen outpatients (mean age ± SD 50.18 ± 11.55 years; 11 females and 5 males) affected by major depression without melancholia (DSM-IV) were included in the study. The control group consisted of 11 healthy volunteers (mean age ± SD 39.90 ± 13.39 years; 2 females and 9 males). Patients were treated with fluvoxamine (FVX) 100–300 mg daily. Clinical assessment was performed using the Hamilton Rating Scales for Anxiety and Depression (HRS-A; HRS-D) and the Clinical Global Impression Scale (CGI) at basal time (T₀), after 4 weeks and after 8 weeks (T8). Plasma and platelet amino acid levels were determined at T₀ in all the subjects and also at T8 in depressed patients. A significant clinical improvement was observed in depressed patients according to the HRS-A (p = 0.004), HRS-D (p = 0.008) and CGI (p = 0.002). A negative correlation (r = –0.53, p = 0.049) was found between platelet levels of valine and HRS-D improvement rate. Patients showed significantly higher tyrosine/large neutral amino acids (LNAAs) and lower tryptophan/LNAAs, ratios which could represent an index of good response to a serotonergic drug like FVX.

Dosing patterns in Europe: Efficacy and safety of risperidone long-acting injectable in doses of 25, 37.5 and 50 mg

Objective. To assess the dose prescription patterns for risperidone long-acting injectable (RLAI) in patients with schizophrenia who participated in the 6-month, open-label Switch to Risperidone Microspheres (StoRMi) trial. Methods. Clinically stable patients requiring a change in medication were converted to RLAI prescribed using clinically-appropriate doses, as determined by treating clinicians. RLAI 25 mg was recommended as the starting dose, although higher initiation doses were permitted if deemed necessary. RLAI was administered intramuscularly every 2 weeks, with dosage adjustments permitted, and continued for a total of 6 months. Efficacy outcomes included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression–Severity (CGI-S). Treatment-emergent adverse events (AEs) were monitored. Results. A total of 1,849 patients were included. Modal dose was 25 mg for 52.9% of patients. At baseline, patients treated with lower RLAI doses were more likely to be female, have shorter disease duration, milder symptoms, and be using less polypharmacy. The strongest predictors that a patient would remain on 25 mg RLAI were baseline PANSS hallucinatory behaviour item score (odds ratio [OR]=0.78), baseline CGI-S score (OR=0.69), female gender (OR=1.56), and country of residence (P<0.001 for all). Efficacy measures improved in all dose groups, with the greatest improvement seen in patients treated with lower doses. AEs were more common in patients treated with 50 mg RLAI (68 vs. 57% with lower doses; P<0.0001), although most AEs were mild to moderate in severity. Conclusion. In this study, 25 mg RLAI was the most commonly prescribed dose. RLAI was effective and well tolerated over the full range of doses.