Massimo C. Mauri

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.

Plasma and Platelet Amino Acid Concentrations in Patients Affected by Major Depression and under Fluvoxamine Treatment

Plasma and platelet levels of 18 amino acids were measured in 29 outpatients (mean age ± SD 47.41 ± 10.85 years; 14 F, 15 M) affected by major depression (DSM IV) and in 28 healthy volunteers (mean age 42.46 ± 14.19 years; 12 F, 16 M). Plasma and platelet levels of amino acids tended to be higher in depressed patients than in healthy controls. In particular, glutamate, taurine and lysine plasma levels and aspartate, serine and lysine platelet levels were significantly higher. Tryptophan/large neutral amino acids ratio (trp/LNAAs) was significantly lower in depressed patients. Fluvoxamine treatment did not influence plasma and platelet levels of amino acids or trp/LNAAs ratio.

Psychopathological and cognitive features in subclinical hypothyroidism

1. To evaluate effective and cognitive dysfunctions in subjects with a marginal form of thyroid hypofunction the authors studied a population of female goiter patients, divided in two groups on the basis of thyroid function: euthyroidism and subclinical hypothyroidism (SCH). 2. The SCH patients were treated with levothyroxine (LT4) in order to obtain euthyroidism, as demonstrated by normalization of the hormonal pattern. 3. Both groups were evaluated with a wide range of psychometric tests (Wechsler memory test, scribble test, reaction times) and psychopathological rating scales (Hamilton rating scales for depression and anxiety, brief psychiatric rating scale) at admission and after 3 months. 4. At admission, a significant decrease in logical memory was found in SCH patients; no differences in affectivity ratings were found between the groups. 5. After LT4 treatment, SCH patients showed a significant improvement in some items of memory performance. 6. In conclusion, when interfering factors relating to the perception of disease were excluded by employing euthyroid goiter patients as a comparison group, SCH appeared associated only with memory impairment, while the impairment of affective functions described in previous studies comparing SCH patients with normal controls was not confirmed. A significant improvement of memory skills was induced by LT4 treatment in SCH patients.

Perfectionism in depression, obsessive-compulsive disorder and eating disorders

High levels of perfectionism have been observed in major depression, anxiety disorders and eating disorders. Though few studies have compared levels of perfectionism across these disorders, there is reason to believe that different dimensions of perfectionism may be involved in eating disorders than in depression or anxiety [Bardone-Cone, A. M. et al. (2007). Perfectionism and eating disorders: Current status and future directions. Clinical Psychology Review, 27, 84-405]. The present study compared patients with major depression, obsessive-compulsive disorder, and eating disorders on dimensions of perfectionism. Concern over Mistakes was elevated in each of the patient groups while Pure Personal Standards was only elevated in the eating disorder sample. Doubts about Actions was elevated in both patients with obsessive-compulsive disorder and eating disorders, but not in depressed patients. Analyses of covariance indicated that Concern over Mistakes accounted for most of the variance in the relationship of perfectionism to these forms of psychopathology.

A single blind comparison of amisulpride, fluoxetine and clomipramine in the treatment of restricting anorectics.

1. The study evaluated the efficacy of amisulpride, fluoxetine and clomipramine at the beginning of the re-feeding phase of the treatment of restricting anorexia nervosa according to DSM-IV criteria. 2. 13 patients, mean weight 37.61 kg +/- 9.80 SD, were treated with clomipramine at a mean dosage of 57.69 mg +/- 25.79 SD; 10 patients, mean weight 40.90 kg +/- 6.98 SD, were treated with fluoxetine at a mean dosage of 28.00 mg +/- 10.32 SD; 12 patients, mean weight 38.41 kg +/- 8.33 SD, were treated with amisulpride at a mean dosage of 50.00 mg +/- 0.00 SD. 3. Clinical evaluation was carried out under single-blind condition at basal time and after three months by a structured clinical interview, the Eating Disorder Interview based on Long Interval Follow-up Evaluation (LIFE II BEI). 4. Patients treated with amisulpride showed a more significant increase (p=0.016) of mean weight. Concerning weight phobia, body image disturbance and amenorrhoea, no significant difference resulted.

Long-term treatment of chronic schizophrenia with risperidone: a study with plasma levels

Twenty-four chronic schizophrenic outpatients with a mean age of 37.21 years +/- 9.96 SD were treated with risperidone (RSP) at the dosage of 2-9 mg/die (mean 4.46 mg/die +/- 1.30 SD, mean 0.06 mg/kg +/- 0.01 SD) for a year. Clinical evaluation was assessed with the Brief Psychiatric Rating Scale (BPRS), Positive and Negative Symptoms Scale (PANSS), Extrapyramidal Side Effects Rating Scale (EPSE) and a checklist for Anticholinergic Side Effects (ACS) at T0, then after 1 (T1), 2 (T2), 3 (T3), 6 (T6), 9 (T9) and 12 (T12) months. RSP and 9-hydroxy-risperidone (9OH-RSP) plasma levels were determined at T12 by the HPLC method. BPRS and PANSS mean values showed a significant improvement during the study. No correlation between RSP dosage (mg/kg) and RSP, 9OH-RSP plasma levels or active moiety resulted. A positive correlation between age and active moiety was observed. A positive correlation between RSP and 9OH-RSP plasma levels was observed. A curvilinear relationship between active moiety and PANSS improvement (%) was observed. Patients with the higher PANSS amelioration showed RSP + 9OH-RSP plasma levels ranging from 15 to 30 ng/mL. RSP seems to be quite an effective drug. It seems, however, difficult to devise appropriate dose schedules and plasma level determination seems to be necessary in some cases.

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.

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.

A Risk-Benefit Assessment of Sulpiride in the Treatment of Schizophrenia

SummarySulpiride is a substituted benzamide with a selective action on receptors of the dopamine D2-like family, and clinical and pharmacological data suggest that it could be considered to be an atypical antipsychotic.Sulpiride penetrates the blood-brain barrier poorly because of its low lipid solubility. It is mainly excreted unchanged in the urine, and accumulation of the drug could occur in patients with renal dysfunction and possibly in elderly patients with declining glomerular filtration rate. At low dosages (50 to 150 mg/day), sulpiride produces a disinhibiting and antidepressant effect, which is probably related to its action on D2 presynaptic autoreceptors, thus facilitating dopaminergic neurotransmission.Data have confirmed the efficacy of sulpiride in patients with acute or chronic schizophrenia during both short and long term treatment, but long term, placebocontrolled trials are still lacking.It is still doubtful whether sulpiride is more effective than typical antipsychotics for the treatment of negative symptoms. Data from clinical studies are controversial; the majority of authors indicate that sulpiride produces a better recovery rate from negative than from positive symptoms at low doses, but it shows a similar efficacy either on negative and positive symptoms at higher doses.The safety profile of sulpiride is similar to that of typical antipsychotics, although the frequency of adverse effects seems to be globally lower. Extrapyramidal reactions appear generally to be mild. Autonomic effects occur less frequently with sulpiride than with typical antipsychotics, showing no clinically relevant influence on cardiovascular parameters and, on the whole, good tolerability in elderly patients.Sulpiride is known to induce prolactin elevation in both serum and CSF, which may be associated with impotence in men and diminished gonadal function in women; these effects appear to be dosage-dependent.Sulpiride can be considered to be an atypical antipsychotic, considering its action on negative, defective symptoms, its partial activity against positive symptoms, and its low incidence of extrapyramidal adverse effects.Sulpiride could find its specific therapeutic role in elderly patients with schizophrenia, as it shows a good margin of safety between therapeutic dosages and toxic concentrations.

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.