Search

Cannabis, cocaine, amphetamines and derivative substances so as hallucinogens and other drugs with psychotomimetic properties has reached an extensive misuse often producing psychotic reactions similar to primary psychotic disease like schizophrenia. In particular cannabis and cocaine use by young people has been increased during these years, and the age of first use is dramatically decreased [1,2].

Background: 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.

The aim of this study was to compare the effects of different antipsychotics on depressive symptoms in schizophrenic patients. The data were drawn from a retrospective, naturalistic, observational study in which 222 subjects diagnosed as being affected by schizophrenia during a re-exacerbation phase received 6 weeks of monotherapy with fluphenazine decanoate, haloperidol decanoate, haloperidol, clozapine, olanzapine, quetiapine, risperidone or l-sulpiride. The Brief Psychiatric Rating Scale (BPRS), Extrapyramidal Side Effects Rating Scale (EPSE) and Anticholinergic Rating Scale (ACS) were administered at baseline and six weeks after the beginning of the study; depressive symptoms were evaluated using the BPRS items "depressive mood" and "guilt feelings". All of the antipsychotic drugs led to improvements in the depressive dimension, but this was statistically significant only in the case of fluphenazine decanoate, haloperidol, olanzapine, risperidone and l-sulpiride. A clinical improvement in the depressive dimension significantly correlated with the severity of the psychotic picture and its amelioration. Female patients were significantly more likely to show an improvement in depressive symptoms. In conclusion, our findings suggest that atypical antipsychotics as a class do not seem to be more effective on the depressive dimension during the course of schizophrenia than typical ones, at least as far as the collected BPRS data are concerned. The only factor that seemed to influence the improvement in depressive symptoms during our study was gender, as females were significantly more likely to improve although there were no between-gender differences in the baseline severity of the clinical picture.

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) (P0.003, P0.02). 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 (P0.05). The SAPS and SANS responders had a significantly higher mean metabolic ratio [MR = (NCLZ/CLZ)] than the nonresponders (P0.01), 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.

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

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 (P0.001 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; P0.0001), 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.

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.

Gabapentin (GBP) is a new anticonvulsant drug that has shown efficacy in the treatment of epilepsy, several neurological disorders (pain syndromes, acquired nystagmus, Huntington’s chorea, amyotrophic lateral sclerosis), and more recently in the treatment of bipolar disorders. The aim of this preliminary study was to assess the efficacy of GBP as a mood stabiliser in bipolar disorders. The adverse events of GBP were also evaluated. 21 outpatients, 13 females and 8 males (mean age ± SD: 51.90 ± 11.51 years) affected by bipolar disorder (BD), in partial remission (DSM IV) and intolerant to lithium, were treated with GBP at a dose ranging from 300 to 2400 mg/day (mean ± SD: 1010.86 ± 268.55mg; 13.81 ± 4.21 mg/kg) for 1 year. Clinical assessments were performed with the Brief Psychiatric Rating Scale (BPRS), the Hamilton Rating Scale for Depression (HRS-D), the Hamilton Rating Scale for Anxiety (HRS-A) and the Manic Rating Scale (MRS) at baseline (T0), after 15 days (T0.5), after 30 days (T1), and then every month for 12 months. Mean HRS-D, HRS-A and MRS scores did not show any significant variation during the study. Only one patient showed a clinical relapse. The most frequent adverse events reported by patients were dizziness (1%), dry mouth (1%) and sedation (0.5%). There was a significant negative correlation between GBP dosage (mg/kg) and HRS-A score. Mean leucocyte and neutrophil counts showed a significant increase during the study. These preliminary data show potential efficacy and good tolerability of GBP in the prophylaxis of BD, but double-blind studies are required.

Depressive disorders can be regarded as recurrent and chronic conditions that may reduce the quality of life and work output of patients. Data on the long-term efficacy of paroxetine appear to indicate that it is an effective maintenance treatment. Our aim was to measure paroxetine concentrations in plasma in order to optimize its clinical efficacy and tolerability during long-term treatment. We studied 35 patients aged 23-70 years, suffering from Major Depressive Disorder (recurrent). These patients received 10-50 mg of paroxetine once a day for one year; they were evaluated at baseline, after 2 weeks and then after 1,2,6,9 and 12 months by BPRS, HRS-D and HRS-A rating scales, and at the same time, any side-effects were assessed and samples for paroxetine plasma determination were also collected. Results confirmed the efficacy and tolerability of paroxetine for long-term treatment. We observed a curvilinear relationship between plasma paroxetine levels and improvement on the HRS-D with greater clinical amelioration at plasma levels between 20 and 70 ng/ml.

A possible relationship between haematological adverse reactions and clozapine (CLZ) metabolism rate was studied. Sixteen chronic schizophrenic outpatients (mean age 34.62 years +/- 7.56 SD) were treated with CLZ, 75-600 mg/daily for 9 weeks. CLZ and norclozapine (NCLZ) plasma levels were determined weekly, contemporarily with blood cell counts. CLZ plasma levels ranged from 25 to 1270 ng/ml (mean 266.27 ng/ml +/- 197.44 SD), while NCLZ plasma levels ranged from 25 to 1280 ng/ml (mean 169.0 ng/ml +/- 127.94 SD). NCLZ/CLZ ratio ranged from 0.13 to 1.72 (mean 0.72 +/- 0.28 SD). Leukocyte count ranged from 5.2 to 18.8 10(9)/l (mean 9.37 10(9)/l +/- 2.94 SD) and neutrophil count ranged from 1.8 to 13.4 10(9)/l (mean 5.73 +/- 2.57 SD). No correlation was found between CLZ dosage and NCLZ plasma levels. Both CLZ and NCLZ plasma levels correlated positively with neutrophil count (CLZ: P = 0.001, r = 0.26; NCLZ: P = 0.01, r = 0.20). The correlation between NCLZ/CLZ plasma level ratio and neutrophil count was significantly negative (P = 0.002, r = 0.25). These preliminary data suggest that the NCLZ/CLZ ratio, as an index of CLZ metabolism, might be a possible risk factor associated with CLZ treatment.

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.

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.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.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.

Sulpiride 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, placebo-controlled 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.

1. Clinical activity, tolerability and kinetic profile of L-sulpiride (200–300 mg/die p.o.) in relation to age, in 14 chronic schizophrenic in patients diagnosed according to DSM III-R, typed as negative forms, were studied. 2. The drug showed Its efficacy in negative forms of schizophrenia, without any significant difference between negative and positive symptoms even if productive symptom scores were quite low already in pre-treatment condition. 3. No more side effects (anticholinergic and extrapyramidal) in elderly patients compared to young/adult ones were reported. 4. No significant differences between young/adult and elderly patients for the various pharmacokinetic parameters (t 1 2 , AUC, Cmax, Tmax, Vd and CI), after acute and multiple dosing, were observed.

Clozapine is an atypical antipsychotic drug that has been demonstrated to be a highly effective treatment for polydipsia in schizophrenic patients. The authors report the first case of a non-schizophrenic patient affected by polydipsia and central pontine myelinolysis who was successfully treated with clozapine. Copyright © 2002 John Wiley & Sons, Ltd.

1. Clinical activity, extrapyramidal side-effects were evaluated in 22 schizophrenic out patients diagnosed according to DSM III and treated with haloperidol decanoate (50-300 mg i.m. monthly dose) for 12 months. 2. BPRS total scores did not show significant fluctuations showing a clinical stability of the patient population. 3. Patients with a duration of illness greater than 10 yrs (Group 2) showed significant (p less than 0.01) higher EPSE total scores compared to those with a duration of illness less than 10 yrs (Group 1). 4. A positive correlation was found between the administered dose and haloperidol plasma levels. 5. Patients from Group 2 reached the steady-state more slowly and showed a lower total L/D ratio compared to those from Group 1. 6. The pharmacokinetic approach seems desirable in order to adjust the dose and avoid schizophrenic relapses.

To evaluate clinical outcomes and the tolerability of 2 weeks' quetiapine (QTP) treatment for hospitalised patients in a naturalistic setting.Patients with schizophrenia (n = 18), drug-induced psychosis (n = 10; 3 cocaine, 4 hashish and marijuana, and 3 all three substances) or borderline personality disorder (n = 13), were diagnosed by two expert clinicians on the basis of an unstructured clinical interview, and were treated with QTP (250-1000 mg/day). The subjects were then clinically assessed at baseline, and after 7 and 15 days, using the Brief Psychiatric Rating Scale, the Positive and Negative Symptoms Scale (PANSS) and the Hamilton Rating Scale for Depression. At the end of the study, plasma QTP levels were determined and examined in relation to clinical outcome and tolerability.The mean scores of each rating scale were significantly lower at the end of the study in the population as a whole, and within each diagnostic group. The percentage improvement was significantly greater in the patients with drug-induced psychosis than in those with schizophrenia (42.4 +/- 9.1% versus 23.6 +/- 13.5%). QTP was well tolerated, and the incidence of extrapyramidal side effects was low. There was a linear correlation between plasma levels and dose/kg of QTP (r = 0.31; p0.05). The improvement in PANSS significantly correlated with plasma levels and dose/kg in each diagnostic category (Spearman's coefficient was 0.75 [p0.01] for schizophrenia and borderline personality disorder, and was 0.68 [p0.05] for drug-induced psychosis).The results suggest that 2 weeks' QTP treatment may improve the clinical outcome of psychotic re-exacerbation phases in different diagnostic categories and indicate that QTP improves clinical outcome in drug-induced psychosis, as QTP levels correlated with the clinical improvement measured by PANSS.

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.

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.

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.

1. 1. A prevalence of depressive symptomatology, ranging from 25% to 80% has been reported during the course of schizophrenia. 2. 2. Depressive symptoms were assessed in 144 schizophrenic patients (DSM IV) during an acute exacerbation phase. 3. 3. Depressive symptoms showed a prevalence ranging from 5. 5% (severe clinical pictures) to 54. 8 % (mild clinical pictures). 4. 4. The authors did not find a correlation between depressive symptoms per se and the presence of negative psychotic symptoms. Depression may be linked not so much to negative symptoms but to the psychotic state itself. 5. 5. Depressive symptomatology concurrently occured with schizophrenic relapses and improved together with the psychotic clinical picture, independently of the neuroleptic drug employed. Haloperidol, haloperidol decanoate and fluphenazine decanoate all showed a similar improvement of depressive symptoms. 6. 6. L-sulpiride showed a trend to be most effective on depressive symptomatology in comparison to the other neuroleptics.

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.

Cholecystokinin (CCK), β-endorphin (BE), and vasoactive intestinal peptide (VIP) in peripheral blood mononuclear cells from 30 drug-naive schizophrenics compared to 22 healthy controls were studied. Patients were evaluated with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of the Negative Symptoms (SANS) at baseline (T0), and after four weeks (T4) in nine patients who were subsequently treated with haloperidol (HL). Neuropeptide concentrations in peripheral blood mononuclear cells (PBMC) were measured at T0 and, for the treated patients, at T4. There was a negative correlation between CCK and SANS baseline scores and a trend for patients who responded poorly to HL (i.e. patients with a prevalence of negative symptomatology) to have lower CCK basal values.

The aim of this study is to investigate whether oxidative stress may represent a pivotal determinant of the altered functional features of platelets in migraineurs during the headache-free period. Twenty-three patients with migraine with aura, free of attack, and 23 healthy volunteers were enrolled for the study. The involvement of an oxidative condition appears confirmed by the statistically significant increase (p

1. Eating disorders can be found in several psychiatric pathologies: schizophrenia, delusional disorder (somatic type), bipolar disorders, major depressive disorder, borderline personality disorder, generalized anxiety disorder, body dysmorphic disorder, somatization disorder and conversion disorder. 2. Although their clinical features have been defined, relatively little is known about the role of neurobiological patterns in the pathogenesis of these disorders. Several CNS neurotransmitters and neuromodulators are involved in the regulation of eating behavior in animals and have been implicated in symptoms such as depression and anxiety often observed in patients with eating disorders. The authors will review some studies on NA, DA, 5-HT, beta-endorphins, CRH, VP, OT, CCK, NPY and PYY involved in eating disorders. Furthermore, we will highlight some of the studies on drug therapy of eating disorders taking into account the effects of these agents on neurotransmitters and neuromodulators. 3. Antidepressant drugs have long been used for anorexia nervosa and bulimia, these disorders been claimed to be affective equivalent. Antidepressant agents seem to be effective in reducing the frequency of binge-eating episodes, purging behavior and depressive symptomatology. It is notable that antidepressant agents have been proved to be effective in patients with chronic bulimic symptoms, even in cases persisting for many years and in patients who had repeatedly failed courses of alternative therapeutic approaches. In all of the positive studies, antidepressant agents appeared effective even in bulimic subjects who did not display concomitant depression. 4. Few controlled studies on use of medications for anorexia nervosa have been published. Central serotonergic receptor-blocking compounds such as cyproheptadine cause marked increase in appetite and body weight. Zinc supplementation or cisapride could be a therapeutic option in addition to psychological and other approaches in anorexia nervosa. 5. There is no therapy as yet which is fully effective in alimentary disorders. Psychotropic drugs give some relief from symptoms, but they cannot cure the disorders. An integrated approach, either pharmacological or psychological, is still recommendable.

The research literature on alternative drug treatments to lithium therapy for the prevention of recurrences in bipolar disorders is discussed. In particular, the data on anticonvulsants (carbamazepine and valproic acid), antidepressants (alprazolam), and calcium channel blockers (verapamil) are reviewed and original data on clonazepam (CLN) are reported. In a preliminary study on six patients with bipolar disorders (DSM-III-R) without a history of psychotic features in which lithium prophylaxis was ineffective, contraindicated, or badly tolerated, CLN was administered in combination with low-dose neuroleptics or antidepressants in all but one case. All subjects were followed for 13 to 34 months. There were no relapses during the observation period with CLN dose regimens ranging from 1.5-8 mg/day p.o. Side effects were minimal and mostly consisted of transient sedation.

Altaraura, Alfredo Carlo, Fedele De Novellis, Massimo C. Mauri and Roberto Gomeni: Plasma and brain pharmacokinetics of mianserin after single and multiple dosing in mice. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1987, 11 : 23–33. 1. 1. Pharmacokinetics parameters describing the time course of concentrations of mianserin (MIA) in plasma and brain and the relationship between plasma and brain concentrations were studied after acute and chronic administration of increasing doses of MIA in adult mice. 2. 2. There was a linear relationship between the area under the curve (AUC), the maximum concentration (Cmax) and doses, in plasma and brain, both during acute and chronic experiments (p 3. 3. A five-fold variation in plasma and brain terminal half-life (t 1 2 ) after chronic administration of the drug was observed, possibly due to a reduction in plasma drug clearance (CL). 4. 4. The values of Cmax and AUC in plasma and brain showed an increase of respectively about three and twelve times after chronic treatment. 5. 5. A very good correlation was observed between plasma and brain Cmax in both acute and chronic experiments; brain Cmax was 10.2 (±0.16) times higher than plasma Cmax after acute administration and 12.08 (± 1.33) times higher after chronic administration.

1. The possible influence of haloperidol and its metabolite plasma levels on clinical outcome in schizophrenic patients was evaluated. 2. 18 schizophrenic inpatients diagnosed according to DSM III, were treated with conventional haloperidol p.o. for four weeks. 3. Plasma levels of haloperidol and its reduced metabolite were measured by mass-spectrometry assay. Clinical outcome was evaluated by BPRS. 4. Cluster analysis only considering BPRS improvement and reduced haloperidol/haloperidol ratio was able to discriminate two groups of patients: one of non responders and the other of responders. The former group presented higher ratios than the latter. 5. Reduced haloperidol/haloperidol ratio could be considered as a good marker for prediction of the clinical outcome.

— A patient suffering from major depression was treated with mianserin for 6 years, with drug plasma monitoring. No relapses or significant side effects occurred during this period.

Seventy five elderly depressed in-patients, ages ranging from 60 to 83 years, diagnosed as Major Depression according to DSM III were treated, under double-blind conditions, with 75 mg Amitriptyline (AMI) (26 patients), 60 mg Mianserin (MIA) (24 patients) or 150 mg Trazodone (TRZ) (25 patients) p.o. for 5 weeks. There were no differences in the clinical outcome between the three groups of patients at the end of the trial, with a significant amelioration (P less than 0.01) at the Hamilton Rating Scale for Depression and Geriatric Depression Scale. TRZ showed a significantly lower incidence of side effects compared to MIA and AMI. Atypical antidepressants, including TRZ, seem more suitable for treating elderly depression than the first generation antidepressants on the basis of risk/benefit ratio considerations.

Clonazepam (CLN), a benzodiazepine originally used as an anti-epileptic, was tested in schizophrenia in a double blind comparison in combination with haloperidol (HL). Twenty-four schizophrenic inpatients, diagnosed according to DSM III were treated with HL and CLN (Group 1) or HL and placebo (Group 2) for 4 weeks. The Brief Psychiatric Rating Scale (BPRS) and the Extrapyramidal Side Effect Scale (EPSE) were used for assessing psychopathological features and extrapyramidal side-effects before treatment and then weekly. No differences in specific schizophrenic symptoms were detected between the two groups, but in Group 1 an early significant BPRS amelioration was noticed compared to Group 2. Moreover, the excitement item improved significantly in Group 1 only, from the second week. Less severe EPSE scores were observed in Group 1 in comparison to Group 2. In conclusion the combination of CLN and HL seems to be preferred to HL alone in cases of psychotic excitement and in order to reduce the severity of extrapyramidal side-effects.

1. The knowledge of the pharmacokinetic profile of fluphenazine decanoate (FPZ-D) suggested it was suitable for treatment of schizophrenic patients not just during the maintenance phase of the disease but also during acute relapses. 2. 27 acute schizophrenic in-patients (diagnosed according to the DSM III) were treated with FPZ-D, 25 mg i.m. with repeated administrations (after 2, 4, 30 days). 3. FPZ-D proved effective in all cases, already after the second day and particularly on Brief Psychiatric Rating Scale items such as delusion, hallucinations, hostility. 4. Extrapyramidal side-effects, appeared in about 40% of the patients. 5. The use of the drug both in the acute phase and maintenance schizophrenia therapy is envisaged, overcoming the problems deriving from the rejection by patients of any therapeutic tool and consequently the therapeutic "milieu".

Authors studied 42 depressed patients of both sexes suffering from Major Depression and Dysthimic Disorder, treated with viloxazine for 4 weeks. All patients were divided into two groups on the basis of their age (Group 1 mean age 45 +/- 2.2 and Group 2 mean age 68.3 +/- 1.12). Viloxazine was effective in different depressive situations, regardless of the age of the patient or the therapeutic context, even if in Group 2 the out-patients did significantly better (p less than 0.01) than the hospitalized ones. Mean steady-state plasma levels and level/dose ratios were significantly higher (p less than 0.05) in elderly patients than in younger ones. No correlation between viloxazine plasma levels-clinical efficacy and side-effects was found even though patients suffering from Major Depression showed a trend to a better response with plasma levels below 5 gamma/ml. The satisfactory antidepressant activity and the good tolerability of viloxazine in elderly depressed patients make this drug particularly suitable for using in ambulant geriatric depressed patients.

Ceruloplasmin(CPN)in 57 cerebrospinal fluid(CSF) samples from 30 children affected by acute lymphoblastic leukemia (ALL)undergoing central nervous system(CNS)prophylaxis with intrathecal methotrexate(MTX)+prednisone(PD)+cytosine arabinoside(Group I)or MTX+PD(Group II), and from patients off therapy for at least 1 year (Group in ) was studied by an immune nephelometric method. Controls were CSFs from adults undergoing myelography for diagno sis of discal hernia. All samples contained less than 6 cells/μl and less than 600 mg/l protein. Whether the decrease of CPN reflects an impaired turnover or an alteration of its immunologic reactvity, remains to be elucitated. A defect in this powerful antioxidant may expose patients to CNS damage by O2 radicals.

Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor MonitorTM polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of −4.1 log10 and −4.3 log10 copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV. (Hepatology 2003;38:1419-1427.)