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Clozapine-related pericarditis is a rare side effect of the drug. We reported the clinical cases of two women, aged 22 and 28 years, affected by schizophrenia with pericarditis symptoms related to clozapine treatment of 200 mg/day. Clozapine was discontinued in both patients, resulting in normalization of the ECG changes, and echocardiography confirmed the progressive disappearance of the pericardial effusion. Interestingly, while inflammatory indices and pro-brain natriuretic peptide (pro-BNP) plasma levels were high in both patients, only one of them showed tachycardia, subjective chest pain, shortness of breath and dyspnea, with a clinical symptomatology suggesting a cardiac involvement. BNP is a vasoactive peptide synthetized by the ventricular myocardium which splits in two fragments: BNP and the N-terminal (pro-BNP). Both are considered valuable biomarkers in clinical practice for the prediction of disease state and prognosis in patients with suspected heart failure. Pro-BNP acts as a key regulator in the homeostasis of water and salt excretion and in the maintenance of blood pressure, mainly by inhibiting the renin-angiotensin-aldosterone axis and blocking the sympathetic nervous activity. In our cases, pro-BNP plasma levels proved to be a profitable way to identify subjects with asymptomatic cardiac impairment who could benefit from a therapy preventing progression to heart failure.

Hyponatremia is occasionally unmasked in psychiatric patients during hospitalization after routine blood and urinary tests, and correlates in most cases with an inappropriate secretion of antidiuretic hormone, mainly due to iatrogenic factors. Only a few studies have regarded the combination of psychotropic drugs as triggers of chronic, asymptomatic hyponatremia in bipolar patients, who require to be hospitalized because of the exacerbation of their mental illness. We presented three clinical cases of patients affected by a long-term psychiatric disorder and under polypharmacotherapy for several months. After excluding other potential factors, we hypothesized that pharmacological treatment with a mood stabilizer (oxcarbazepine) associated with a benzodiazepine (delorazepam), a second-generation antipsychotic (olanzapine) or an antidepressant (fluvoxamine), triggered severe hyponatremia ([Na+] ≤125 mEq/L), serum hypo-osmolarity, and elevated inappropriate urine osmolarity added to more diluted sodium concentration. When we discontinued the treatment, clinical conditions of our patients improved, despite the previous administration of hypertonic saline jointly with water restriction. Psychiatrists should consider that bipolar patients on long-term polypharmacotherapy may present a higher risk of severe hyponatremia not clinically detectable. Consequently, routine laboratory tests should be periodically repeated as they represent the only available tool to unmask such electrolyte imbalances.

Background:The decision to adopt forced medication in psychiatric care is particularly relevant from a clinical and ethical viewpoint. The European Commission has funded the EUNOMIA study in order to develop European recommendations for good clinical practice on coercive measures, including forced medication.Methods:The recommendations on forced medication have been developed in 11 countries with the involvement of national clinical leaders, key-professionals and stakeholders’ representatives. The national recommendations have been subsequently summarized into a European shared document.Results:Several cross-national differences exist in the use of forced medication. These differences are mainly due to legal and policy making aspects, rather than to clinical situations. In fact, countries agreed that forced medication can be allowed only if the following criteria are present: 1) a therapeutic intervention is urgently needed; 2) the voluntary intake of medications is consistently rejected; 3) the patient is not aware of his/her condition. Patients’ dignity, privacy and safety shall be preserved at all times.Conclusion:The results of our study show the need of developing guidelines on the use of forced medication in psychiatric practice, that should be considered as the last resort and only when other therapeutic option have failed.

The transient splenial lesion (TSL) of the corpus callosum (CC) is an uncommon radiologic finding incidentally detected on Magnetic Resonance Imaging (MRI). It was first observed in epileptic patients and ever since it has been described in varied neurologic conditions but its etiology is still little known. Slow disappearance of signal abnormalities in the CC mainly occurs after some weeks or months and then TSL carries a good prognosis making unnecessary invasive therapies and procedures. We report a case of an isolated TSL of CC in a patient suffering from psychotic and hormonal disorders, which spontaneously resolved within only one week.

Blood dyscrasias excluding agranulocytosis received limited attention in antipsychotic-treated patients during the first 18 weeks of therapy, although severe clinical conditions have been reported in a few cases. We extracted data records of 285 Caucasian patients after 18 weeks of antipsychotic treatments to investigate risk factors of blood dyscrasias. We observed a higher risk to develop both transient and persistent anemia, neutrophilia and eosinophilia in clozapine-treated patients, whereas in those treated with other atypical antipsychotics when compared to a reference group under typical antipsychotics, emerged an increased risk for transient neutrophilia and eosinophilia. Male patients revealed a higher risk of persistent eosinophilia, neutrophilia, and leukocytosis. Concomitant treatments with mood stabilizers or benzodiazepines proved to be risk factors for transient anemia, antidepressants for transient eosinophilia. Severe complications emerged in 3 cases of agranulocytosis. Cross-tabulation analysis showed a higher probability of a poor response in clozapine-treated patients with persistent anemia and a positive with persistent neutrophilia and eosinophilia. Our data evidenced that emerging blood dyscrasias were not associated with critical adverse effects, and only agranulocytosis required a treatment interruption. Other atypical antipsychotics might represent a viable alternative to potentially harmful clozapine and typical antipsychotics at the onset of life-threatening haematological alterations.

Safety and tolerability of mood stabilisers are major clinical concerns when used in bipolar patients. Side effects of lithium and some antiepileptics have been reviewed in the context of a spontaneous reporting database over the last 10 years (FDA database and published reports). During pregnancy, antiepileptics show great concerns, and adverse events are all related to childbirth, whilst congenital abnormalities are not higher than previously estimated. Cutaneous adverse reactions are the most prevalent in children and adolescent. In adult lithium-treated patients, nephrotoxicity is still a major problem; the combination with carbamazepine and valproate can increase the risk of hypothyroidism. Hyperparathormonemia and hypercalcaemia are unrecognised and underappreciated adverse effects. Acute exacerbation of psoriasis is still a major problem, and the risk of skin reactions with eosinophilia and systemic symptoms is higher when mood stabilisers are used concomitantly; when associated with antipsychotics, the risk of pneumonia is possible (highest risk for olanzapine plus carbamazepine). A decrease in total body water and the decline of glomerular fi ltration rate represent the main lithium adverse effects in elderly patients. Long-term treatment is associated with impairment in immediate verbal learning and memory and creativity performance. Antiepileptics display signifi cant adverse events (hyponatraemia, cardiac toxicity) and the risk of multiple drug-drug interactions is very high. Cumulative exposure to antipsychotics and mood stabilisers can be associated with vascular stiffness (elevated systolic blood pressure), hypertriglyceridaemia, insulin resistance and low HDL cholesterol. In light of the above considerations, clinicians should continuously and further assess risks and benefi ts of mood stabilisers when treating bipolar patients.

Objective: We conducted the first pilot Italian study to assess the preventability of adverse drug reactions involving psychotropic drugs reported through spontaneous reporting system from 01/07/2012 to 31/12/2014 in Campania Region. Methods: Preventability was assessed, case-by-case, using an adapted version of the P-method. The evaluation was performed only for those reports that had, as suspected drug, antipsychotics, mood stabilizers, antidepressants, anxiolytic and/or sedative-hypnotic. Results: Eighty-one cases (19.2%) out of 421 reported during the study period were preventable. In seventy-seven (95.1%) out of 81 preventable cases, the underlying mechanism of the adverse drug reactions was dose-related, in four (4.9%) preventable cases the underlying mechanism of the adverse drug reactions was respectively susceptibility- (1; 1.2%), unknown- (1; 1.2%) and time-related (2; 2.5%). In the 81 preventable cases, 97 critical criteria were detected of which 29/97 (29.9%) related to healthcare professionals’ practices, 0/97 (0.0%) to drug quality and 68/97 (70.1%) to patient behaviour. Conclusions: We proved that it was possible to apply and adapt the P-Method to assess the preventability of the adverse drug reactions involving psychotropic drugs, analysing individual case safety report sent through Campania Region spontaneous reporting system. Information acquired will be used to organize educational activities for both physicians and patients to promote a more appropriate drug use.

The effects of olanzapine and haloperidol on metabolic parameters in bipolar patients have been evaluated much less comprehensively than in schizophrenic patients. Therefore, in this study, medical records of 343 schizophrenic and bipolar patients treated with haloperidol or olanzapine for 1 year were retrospectively reviewed and metabolic outcomes were evaluated. After 12 months of follow-up, 25.9% of patients showed ≥3 metabolic abnormalities with a point prevalence of 27.2% in the bipolar and 24.9% in the schizophrenic group: 22.0% of the schizophrenic patients treated with haloperidol and 29.8% of those treated with olanzapine achieved ≥3 metabolic alterations; in bipolar patients, these percentages were 15.8% of those treated with haloperidol and 37.8% of those treated with olanzapine (p < 0.0001). Significant changes were reported over time in fasting glucose, triglycerides and cholesterol blood levels, systolic and diastolic blood pressure, body weight, and BMI. Overall, a significant number of schizophrenic and bipolar patients treated with olanzapine showed ≥3 metabolic alterations in the first month of treatment when compared to those treated with haloperidol. Moreover, the number of olanzapine-treated patients developing metabolic changes in the first month was significantly higher in both diagnostic groups when compared to those who reached metabolic abnormal values in the subsequent 11 months. These data suggest that both antipsychotics could increase the metabolic risk in schizophrenic and bipolar patients with a higher prevalence in olanzapine-treated patients. On the other hand, olanzapine-treated patients seem to achieve metabolic abnormalities faster than haloperidol-treated subjects in both diagnostic groups.

Adiponectin is a recently discovered peripheral peptide that is secreted exclusively by differentiated adipocytes. It has been shown to enhance insulin sensitivity, control body weight, regulate lipid homeostasis, and prevent atherosclerosis. Dysregulation of both lipid and glucose metabolism and changes in body weight and body fat mass have been reported in bulimia nervosa (BN) and/or binge eating disorder (BED); hence, investigation of adiponectin secretion is of obvious interest in these eating disorders. To this purpose, we measured plasma levels of adiponectin, glucose, cholesterol, triglycerides, and thyroid hormones in 60 drug-free women, including 20 patients with BN, 20 patients with BED, and 20 healthy controls. Compared with healthy women, BN women exhibited significantly increased circulating adiponectin levels (P < 0.002) and cholesterol concentrations (P < 0.005), whereas BED women had significantly reduced plasma levels of adiponectin (P < 0.005) and increased concentrations of glucose (P < 0.01), cholesterol (P < 0.05), and triglycerides (P < 0.02). Moreover, plasma levels of adiponectin were significantly correlated to the frequency of binge/vomiting episodes (r = 0.65, P = 0.002) in bulimics but not to the frequency of bingeing in BED patients. Because we did not include a group of obese patients who did not binge eat, the specificity of our findings in the BED should be considered cautiously. However, on the basis of present results, it is tempting to speculate that the increased production of adiponectin in BN may represent a compensatory mechanism to counteract the possible development of insulin resistance, whereas the decreased secretion of adiponectin in individuals with BED may be a risk factor for the development of glucose intolerance.

Background. Ghrelin and leptin are endogenous peripheral proteins involved in the regulation of eating behaviour. In particular, ghrelin stimulates hunger and promotes food ingestion, whereas leptin increases satiety and reduces food consumption. Therefore, alterations in the physiology of these peptides may play a role in the pathogenesis of eating disorders such as bulimia nervosa. In the present study, we investigated ghrelin and leptin responses to food ingestion in patients with bulimia nervosa.Method. Nine symptomatic drug-free bulimic women and 12 age-matched healthy women ingested a meal of 1207 kcal (60% carbohydrates, 23% fat and 17% proteins) at 12.00 a.m. and underwent blood sample collection before and 45, 60, 90, 120 and 180 min after the meal. Plasma levels of ghrelin, leptin, insulin and glucose were measured.Results. In healthy women, circulating ghrelin exhibited a drastic decrease after the food intake whereas, in bulimic patients, this response was significantly blunted. No difference between the two subjects groups was observed in post-prandial profiles of plasma leptin, insulin and glucose.Conclusions. The lack of a leptin response to food ingestion, in both bulimic and healthy women, is compatible with the role of this peptide as long-term rather than short-term modulator of eating behaviour. The blunted ghrelin response to food ingestion may support the occurrence in bulimic subjects of an impaired suppression of the drive to eat following a meal. This may have implications for binge-eating.

Anecdotal evidence tends to favour olanzapine in the treatment of hallucinations in patients with schizophrenia spectrum disorders; however, no conclusive evidence is available on this topic. We report here a clinical case in which a 46-year-old man, suffering from a schizoaffective disorder (depressed type), underwent olanzapine treatment (20 mg/day). After inducing an initial amelioration, the patient had a re-exacerbation of auditory hallucinations and a clinical and psychosocial worsening, which subsided after olanzapine discontinuation. Olanzapine may induce a worsening of hallucinations in a psychotic disorder with substantial affective component and therefore its use should be carefully evaluated in such cases.

Cannabis may play a causal role in the onset of some schizophrenia cases; however, the biological vulnerability that predisposes some individuals to develop schizophrenia after exposure to cannabis is not known. According to the diathesis-stress pathogenetic model, it is likely that the endogenous stress response system, including the hypothalamus–pituitary–adrenal (HPA) axis, could be involved. Therefore, we investigated the saliva cortisol awakening response (CAR) of 16 patients with schizophrenia onset after the exposure to cannabis (Can+) as compared to 12 patients with schizophrenia onset without cannabis exposure (Can−) and to 15 healthy controls. The CAR was assessed by collecting saliva samples at awakening and after 15, 30 and 60 min. As compared to healthy controls, Can+ schizophrenia patients exhibited significantly enhanced baseline saliva cortisol levels and a flattened CAR. No significant abnormality in both baseline cortisol levels and CAR was detected in Can− schizophrenia patients. These findings demonstrate a dysregulation of the HPA axis in chronic schizophrenic patients whose illness started after cannabis exposure but not in those with an illness onset without cannabis exposure. Further studies need to clarify whether this HPA dysregulation is a part of the biological background underlying the increased risk to schizophrenia after exposure to cannabis.

Plasma levels of clozapine and its major metabolites, N-desmethylclozapine and clozapine-N-oxide, were measured in 18 schizophrenic patients at different times (4, 6 and 24 weeks) during the course of treatment with multiple doses of the drug, by using high performance liquid chromatography (HPLC) with UV detection. Plasma levels of clozapine and N-desmethylclozapine were significantly higher in females than in males after 4 and 6 weeks, but not after 24 weeks, of treatment. No sex difference was found at any time with respect to plasma levels of clozapine-N-oxide.

RNase protection assay and in situ hybridization were used to analyze the temporal and cellular changes in nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) mRNA content evoked by the lipophilic β-adrenergic receptor agonist clenbuterol in adult rat brain. Clenbuterol elicited a threefold increase in NGF mRNA expression which was limited to the cerebral cortex. This increase was maximal at 5 h, still evident by 10 h, and declined to control levels by 24 h. By 10 h NGF protein was also increased. Elevated NGF mRNA hybridization following clenbuterol was localized in the superficial cortical layers II and III in large Nissl-pale cells, suggesting that NGF mRNA induction occurs in neurons. In the same animals, clenbuterol induced a twofold increase in the levels of bFGF mRNA in cerebral cortex and hippocampus. This increase was localized primarily in glial cells as demonstrated by bFGF mRNA hybridization over all cortical regions and by labeling of the stratum lacunosum moleculare of the hippocampus. Our results suggest that enhanced noradrenergic tone regulates expression of these two trophic factors by different synaptic mechanisms and suggest that neurotransmitter(s) can coordinate trophic influences on different cell populations.

Recent evidence supports the use of second generation antipsychotics in drug resistant depression. The aim of the present open-label study was to evaluate the effect of aripiprazole as an add-on medication in drug-resistant depressed patients who had not responded to clomipramine. Thirty-five patients with major depressive disorder (MDD) were included in the study. All patients had not responded to a previous adequate treatment with an SSRI and had been receiving clomipramine (daily doses ranging from 100 to 300 mg) for 113.9 ± 18.9 days without getting significant clinical improvement. Aripiprazole was added at the fixed dose of 5mg/day and clinical status as well as clomipramine plasma levels were monitored before and after 4, 8, and 24 weeks of combined treatment. Hamilton depression rating scale scores significantly decreased over the follow-up period with 91.4% and 34.3% of patients getting a response or a remission, respectively, after 24 weeks of combined treatment. No worsening of clomipramine-related side effects nor new side effects were observed. The clinical improvement was accompanied by a progressive and significant increase in clomipramine plasma levels. With the limitation of an open-label design, these data suggest for the first time the putative efficacy and safety of aripiprazole in combination with a tricyclic medication in drug resistant depressed patients. The role of the observed pharmacokinetic interaction in the mechanism of aripiprazole antidepressant activity remains to be proved.

Available evidence about the relationship between poor insight and other clinical characteristics in patients with obsessive–compulsive disorder (OCD) is inconclusive and conflicting. There is also a paucity of data on the long-term course and treatment outcome of OCD patients with poor insight. The present study reports the findings of a relatively large sample (n=106) of outpatients fulfilling DSM-IV criteria for OCD, treated with serotonin reuptake inhibitors (SRIs) and prospectively followed up for 3 years. Baseline information was collected on demographic and clinical characteristics, using standardized instruments. Insight was assessed by means of the Brown Assessment of Beliefs Scale (BABS). Eighty-three patients were followed prospectively and evaluated systematically by validated measures of psychopathology. Compared to their good insight counterparts, the OCD patients with poor insight (22%) showed a greater severity of obsessive– compulsive and depressive symptomatology; an earlier age at onset; a higher rate of schizophrenia spectrum disorder in their first-degree relatives; a higher comorbidity with schizotypal personality disorder. During the follow-up period, poor insight OCD patients were less likely to achieve at least a partial remission of obsessive–compulsive symptoms; required a significantly greater number of therapeutic trials; received more frequently augmentation with antipsychotics. The results suggest that the specifier “poor insight” helps to identify a subgroup of patients at the more severe end of OCD spectrum, characterized by a more complex clinical presentation, a diminished response to standard pharmacological interventions, and a poorer prognosis. Further research is needed to identify alternative strategies for the management of these patients.

Anecdotal evidence tends to suggest clozapine treatment as a cause of leucocytosis in schizophrenic patients, however, no conclusive evidence is available on this topic. We report the clinical cases of two schizophrenic men who were diagnosed with clozapine-related leucocytosis. The clozapine treatment was performed at a dose between 200 and 400 mg/day. When leucocytosis appeared, there was a loss of response to clozapine in both patients. Clozapine-induced leucocytosis in schizophrenic patients could be correlated to occurrence of psychotic symptomatology.

Background. Several lines of evidence indicate a role of the brain-derived neurotrophic factor (BDNF) in the modulation of eating behaviour. Therefore, alterations in the physiology of this neurotrophin may be involved in the pathogenesis of eating disorders. In the present study, we investigated serum levels of BDNF in patients with anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED).Method. Ninety-nine drug-free women (27 with AN, 24 with BN, 24 with BED and 24 healthy controls) underwent both a blood sample collection in the morning and diagnostic and psychopathological assessments by means of structured clinical interviews and ad-hoc rating scales. Serum levels of BDNF, 17β-oestradiol, FT3 and FT4 were measured.Results. Compared to healthy controls, serum levels of BDNF were significantly reduced in underweight AN women and in normal weight BN women, but not in overweight BED women. Changes in circulating BDNF levels were not affected by the presence of co-morbid depressive disorders. No significant correlation emerged between neurotrophin concentrations and psychopathological, nutritional, demographic and hormonal variables.Conclusions. These findings evidentiate alterations in serum BDNF levels in malnourished patients with AN or BN, but not in well-nourished individuals with BED. Since BDNF seems to exert a satiety effect, its reduction may represent an adaptive change to counteract the decreased calorie ingestion of AN and BN individuals.

Ghrelin is a peripheral gastric peptide involved in the regulation of eating behavior and energy homeostasis. While changes in ghrelin plasma levels have been found in anorexia nervosa, bulimia nervosa (BN) and obesity, no study has assessed circulating ghrelin in binge eating disorder (BED). Therefore, we measured plasma levels of this peptide in women with BED as compared to women with BN, obesity and healthy controls. One hundred and eighty-two drug-free women (56 bulimics, 13 non-obese and 34 obese BED subjects, 28 obese non-binge eating women and 51 non-obese healthy women) underwent psychopathological and nutritional assessments and blood sample collection for glucose and ghrelin assays in the morning. As compared to non-obese healthy women, both non-obese and obese BED women as well as obese non-binge eating women had significantly increased values of body weight, body mass index and body fat mass. Moreover, plasma ghrelin concentrations were significantly decreased in both non-obese (P

BACKGROUND: Gut-derived peptides, such as peptide YY (PYY) and ghrelin that regulate the initiation and termination of meals, could play a role in the altered eating behavior of patients with bulimia nervosa (BN). Therefore, we aimed to assess plasma PYY and ghrelin responses to a test meal in symptomatic bulimics. METHODS: Ten healthy women and nine women with BN underwent blood sample collections before and after the ingestion of a test meal of 1300 Kcal (with 15% carbohydrates, 10% proteins, and 75% fat) at 12:00 noon. Plasma total PYY, ghrelin, insulin, and glucose were assayed. RESULTS: As compared with healthy women, bulimics exhibited a significantly blunted increase of circulating PYY (p < .007) and a significantly reduced suppression of plasma ghrelin (p < .0004) after the test meal. No significant differences emerged in food-induced plasma insulin and glucose changes between the two groups. Plasma ghrelin suppression after the meal was significantly correlated with plasma PYY increase. CONCLUSIONS: We replicated our previous findings of an altered ghrelin response to food ingestion in people with BN and showed for the first time a blunted PYY increase after food consumption in these patients. These findings support the occurrence in BN of a profound dysregulation of some peripheral regulatory mechanisms involved in the short-term regulation of feeding behavior that might be involved in the pathophysiology of their binge eating behavior

Sir—Selective serotonin reuptake inhibitors (SSRIs), alone or in combination with different psychotherapies and/or nutritional counselling, have been proved to reduce binge eating and vomiting frequencies in patients with bulimia nervosa (BN). However, percent reductions in bingeing and purging range from 18 to 87%.1 It has been suggested that the initial capacity, affinity or genotype of proteins involved in the regulation of SSRI action could account for differences in treatment outcome.2 The 5-HT transporter (5-HTT) represents the prime target of SSRIs, and a long (L) and a short (S) variant of the promoter region of the 5-HTT gene, with different transcriptional efficiencies, have been identified.3 The S allele of the 5-HTT gene-linked polymorphic region (5-HTTLPR) has been associated with poorer SSRI response in major depression.2, 4, 5, 6, 7

Clozapine has been shown to acutely increase the rat brain and plasma concentrations of the neuroactive steroids 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) or allopregnanolone and THDOC, 2 positive allosteric modulators of GABA-A receptors. Hence, it has been suggested that this effect could underlie the therapeutic efficacy of this drug, contributing to its atypical profile. So far, no study assessed whether the effects on neurosteroids reported in the experimental animal occur also in humans. Therefore, we measured plasma levels of 3alpha,5alpha-THP and THDOC in a sample of drug-resistant schizophrenic patients before and after 1, 2, 4, 6, 8, 12, and 24 weeks of clozapine administration (600 mg/d by the end of the 6th week). No significant changes in circulating concentrations of 3alpha,5alpha-THP and THDOC were observed in the course of clozapine administration in spite of the patients' good clinical response to the drug. These findings provide evidence, for the first time, that clozapine is not able to affect morning circulating levels of 3alpha,5alpha-THP and THDOC in humans. Therefore, although we cannot exclude that changes in neuroactive steroids could occur immediately after the daily administration of clozapine as in the experimental animal, our data support the view that the therapeutic efficacy of this atypical antipsychotic is not linked to changes in the baseline concentrations of peripheral 3alpha,5alpha-THP and THDOC.

The relationship between the time course of clinical response to clozapine and the time course of clozapine plasma levels has never been investigated. In the present study, we assessed prospectively the clinical response to clozapine and the plasma levels of the drug and its major metabolites in 32 drug-resistant patients with schizophrenia kept on a fixed dose of 600 mg/day for 1 year Four of the patients met response criteria at week 4 of treatment. At weeks 8, 12, and 24, new responders were 7, 6, and 6, respectively. Nine patients never achieved clinical response. In responders at week 4, clozapine and clozapine-N-oxide plasma levels were significantly higher than in both new responders at weeks 8, 12, and 24 and nonresponders. In new responders at weeks 8, 12, and 24, in spite of a fixed clozapine daily dose, mean drug plasma levels progressively rose up to when clinical response occurred; then, the levels remained stable over time. Nonresponders exhibited mean clozapine plasma levels constantly below the value of 260 ng/ml, with N-demethylation as the preferred metabolic route. The present findings show, for the first time, that the time course of the clinical response to clozapine may be linked to the time course of plasma levels of clozapine and its major metabolites.

Weight gain is a widely reported side effect of clozapine, but no predictive factor has been identified so far. We investigated whether pretreatment values of circulating leptin or its early changes during clozapine administration could predict the long- term weight gain induced by the drug. Body weight and plasma levels of leptin were prospectively measured in 22 patients (13 men and 9 women) with drug-resistant schizophrenia undergoing a long-term treatment with clozapine. At the end of the second week of clozapine administration, circulating leptin increased much more than weight gain, and this increase was inversely correlated to body weight increase observed after 6 and 8 months of treatment. These findings suggest that early changes in leptin secretion may predict long-term weight gain in the course of clozapine administration.

Peripheral amino acid changes have been reported in schizophrenia, but results are not consistent. We measured serum levels of different amino acids in 11 neuroleptic-resistant schizophrenic patients before and after clozapine treatment and in 11 age- and sex-matched healthy subjects. The schizophrenic patients exhibited significantly higher levels of serum aspartate, glutamate, isoleucine, histidine and tyrosine and significantly lower concentrations of serum asparagine, tryptophan and serine. In patients, the ratio between tryptophan and large neutral amino acids (LNAA) was significantly lower than in matched controls, whereas the tyrosine/LNAA ratio did not differ significantly. Moreover, 12 weeks of clozapine administration significantly reduced serum levels of glutamate but did not restore the values observed in normal controls, nor did it affect other amino acid concentrations. These data show changes in serum amino acids that may influence central serotonergic, dopaminergic and glutamatergic transmission in neuroleptic-resistant schizophrenics.

Leptin is known to regulate body weight, energy balance, and reproduction. Therefore, investigation of its physiology is of obvious interest in bulimia nervosa (BN), an eating disorder characterized by body weight-related psychopathology, acute changes in the energy balance, and reproductive alterations. To date, the few studies that have assessed leptin production in BN have had several limitations, including the measurement of blood leptin levels in treated patients and the lack of normal weight healthy controls, so that the information they provide is not conclusive. As the investigation of leptin dynamics is likely to be more informative, we decided to assess leptin response to acute fasting and refeeding in both untreated patients with BN and healthy controls. Twelve women meeting the diagnostic criteria for BN of the Diagnostic and Statistical Manual of Mental Disorders, and 10 healthy women of the same age range participated in a 3-day study. At 1800 h on day 1, they received a meal of 1088 Cal, with 53% carbohydrates, 17% protein, and 30% fat. Then, they fasted until 1800 h on day 2, when they received the same meal. On day 3, they received a standard hospital diet of 2600 Cal, divided into 3 meals, with the same percentages of nutrients as described above. Blood samples were collected at different time points for plasma leptin, glucose, and insulin measurements. In bulimic patients, plasma leptin values were significantly lower than in healthy women (P < 0.0001) and were positively related to body weight, expressed as body mass index (r = 0.86; P < 0.0001). The leptin response to the fasting/refeeding paradigm significantly differed between patients and controls (time × group interaction, P < 0.0001). In fact, in healthy subjects, acute fasting induced a 58% decline in the plasma leptin concentration, whereas such a decrease was only 7% in bulimic women (P < 0.001). After acute refeeding, plasma leptin increased in both groups, although in the patients it did not reach the absolute values observed in normal controls. No significant difference was observed between bulimics and controls in plasma insulin response to the fasting/refeeding paradigm, whereas an abnormal increase in blood glucose levels was observed in the patients after the first meal following acute fasting. We conclude that in untreated women with BN, leptin, despite its very low plasma values, still holds its function as a sensor of body weight changes, but loses its role of signaling acute changes in energy balance.

Immune changes may occur in patients with anorexia nervosa (AN) or bulimia nervosa (BN), and a role for proinflammatory cytokines has been proposed in the pathogenesis of both disorders. We measured plasma levels of interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), soluble forms of the cytokine receptor proteins gp130 and leukemia inhibitory factor receptor (LIF-R), the anti-inflammatory Clara cell 16-kD protein (CC16), prolactin (PRL), cortisol and 17 beta-estradiol in 21 anorexic women, 21 bulimic women and 21 healthy females. As compared to healthy subjects, anorexics exhibited significantly increased plasma levels of gp130 and LIF-R, whereas bulimics had significantly decreased blood concentrations of CC16. No significant differences emerged in the blood levels of the remaining immune parameters. Both patient groups manifested higher plasma levels of cortisol and reduced plasma concentrations of PRL and 17 beta-estradiol. In anorexics, a significant negative correlation was found between plasma levels of gp130 or LIF-R and the body mass index. These findings do not support the hypothesis that proinflammatory cytokines may play a pathogenetic role in eating disorders.

The effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites was studied in 10 schizophrenic patients with residual negative symptoms. Patients stabilized on clozapine therapy (200-450 mg/day) received additional fluoxetine (20 mg/day) for eight consecutive weeks. During fluoxetine administration, mean plasma concentrations of clozapine, norclozapine and clozapine N-oxide increased significantly by 58%, 36% and 38%, respectively. There was no difference in negative symptomatology, as measured by the Scale for Assessment of Negative Symptoms, and the drug combination was generally well tolerated. The concomitant elevation in plasma levels of clozapine and its major metabolites suggests that fluoxetine inhibits the metabolism of clozapine by affecting pathways other than N-demethylation and N-oxidation. Close monitoring of clinical response and, possibly, plasma clozapine levels is recommended whenever fluoxetine is given to patients stabilized on clozapine therapy.

To investigate immune system function in obsessive-compulsive disorder (OCD) we measured plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) in 14 drug-free obsessive-compulsive patients and 14 matched healthy controls. No significant differences were observed between patients and controls in plasma levels of IL-1 beta and IL-6, whereas plasma levels of TNF-alpha were significantly lower (p = 0.001) in the former. Blood levels of prolactin did not differ between the two groups, whereas plasma cortisol concentrations were significantly higher in patients than in healthy subjects (p = 0.02). No significant correlation was found between immune parameters, on the one hand, and endocrine or psychopathological measures on the other. These results suggest that OCD is associated with a decreased production in TNF-alpha, but normal synthesis of IL-1 beta and IL-6.

Steady-state plasma levels of mianserin, amitriptyline, and nortriptyline were determined by HPLC in two groups of elderly depressed patients who underwent a 5-week treatment with mianserin (60 mg/day in three oral doses) or amitriptyline (75 mg/day in three oral doses). Both treatments proved to be effective in reducing depressive symptoms. In the mianserin group, responder patients had steady-state plasma concentrations of mianserin higher than nonresponders. No relationship was found between amitriptyline, nortriptyline, or amitriptyline+nortriptyline plasma levels and clinical response in amitriptyline treated patients.

At two weeks post-transplantation, sciatic nerves inserted into the lesioned septo-hippocampal pathway contain NGF levels more than twice that of normal nerves. These transplanted nerves also contain regenerating cholinergic axons. Moreover, transplanted animals exhibit septal NGF levels that are significantly greater than in animals with lesions only. These results suggest a role for NGF in the ingrowth of axons into the transplants and in the increase in ChAT(+) septal neurons previously observed at this post-transplant time.

Beta-nerve growth factor (NGF), the most well-characterized neuronal trophic factor, appears to have a physiological role in the central nervous system (CNS). This has been suggested by a variety of evidence, including the discovery of NGF mRNA and NGF receptor mRNA molecules in various brain areas (Buck et al., 1987; Large et al., 1986; Whittemore et al., 1987). Furthermore, it has been shown that NGF has trophic influence on cholinergic neurons of the basal forebrain (Fisher et al., 1987; Hefty, 1986; Kromer, 1987; Williams et al., 1986). These findings have suggested the use of NGF as a specific treatment regimen to slow or reverse the progression of neurodegenerative diseases such as Alzheimer’s. However, due to its inability to cross the blood brain barrier, NGF cannot be easily used as a therapeutic approach in the treatment of CNS disorders, therefore, other strategies have been proposed. One alternative is the implantation in the brain of genetically modified cells that produce NGF (Rosemberg et al., 1988). However, significant questions still remain concerning the potential applications of grafted cells to brain pathophysiology. Problems include the potential limited survival time as well as a possible host-immune response to the implant. Another alternative is a more physiological approach, such as enhancing the production of endogenous NGF by pharmacological manipulations. Therefore, informations on the mechanism of NGF biosynthesis regulation are needed.

Pemphigus is a rare autoimmune dermatological disease, whose onset and course depend on the interaction between predisposing severed and inducing factors. Psychological stress has been suggested to be a potential triggering factor of pemphigus. However, this hypothesis has not been thoroughly investigated. To this purpose, we explored recent stressful life events and personality disorders in 25 consecutive subjects with pemphigus. Baseline information was collected on demographic characteristics, family history, presence of psychopathology, the impact of stressful life events occurring within one year prior to onset of pemphigus, presence of Axis I and Axis II diagnosis, using standardized instruments. Patients affected by pemphigus were matched for number, age and gender with subjects with other skin diseases and with healthy volunteers. All pemphigus patients had a negative anamnesis for Axis I diagnosis. Pemphigus patients showed a significantly higher Comprehensive Psychopathological Rating Scale (CPRS) and depression and anxiety with Montgomery-Asberg Depression Rating Scale (MADRS) total scores than controls. Cases and controls did not differ regarding the total number of stressful events experienced. The uncontrollable events and undesiderable events had occurred more frequently among pemphigus patients than controls. In 68% of pemphigus patients at least one personality disorder was diagnosed; there was a high prevalence of obsessive-compulsive and avoidant personality disorder. These findings suggest that stressful life events might increase vulnerability to pemphigus and that personality features might modulate individual susceptibility to illness.

Bilateral (3 nmol/side) i.c.v. infusion of ethylcholine aziridinium ion (AF64A) causes a 70% decrease of hippocampal acetylcholine content lasting for longer than 30 days without changing the density of hippocampal recognition sites for muscarinic ligands. In hippocampal slices prepared from rats receiving i.c.v. AF64A, the activation of phosphoinositide turnover or the inhibition of cyclic AMP accumulation elicited by muscarinic receptor agonists is facilitated. This AF64A treatment also causes a long-lasting decrease of hippocampal norepinephrine and serotonin (5-HT) content. Even a smaller dose of AF64A (1.5 nmol/side) reduces the hippocampal 5-HT content. The number of alpha-1 adrenoceptor recognition sites is slightly increased by 3 nmol/side of AF64A and the stimulation of phosphoinositide turnover by norepinephrine is facilitated. In contrast the decrease of hippocampal 5-HT concentration elicited by AF64A fails to change the 5-HT receptor indices that were measured. These results indicate that in rat hippocampus muscarinic receptors and alpha-1 adrenoceptors are denervated by AF64A and that this denervation promotes a receptor supersensitivity. These results also suggest that we could not find appropriate conditions to express a complete specificity of AF64A in destroying cholinergic axons and therefore this drug cannot be used readily to induce a selective deficiency of central cholinergic transmission.