Plasma amisulpride levels in schizophrenia or schizoaffective disorder.

The atypical antipsychotic drug amisulpride is a benzamide with specific antagonistic properties, which target dopamine D(2) and D(3) receptors, preferentially in the limbic system. Amisulpride is readily absorbed from the gastrointestinal tract, distributed to all body systems with little binding to plasma proteins. Elimination occurs mainly through the kidneys as unchanged drug. In contrast, hepatic metabolism is of minor significance and primarily yields two inactive metabolites. Very little is known about the plasma concentrations of amisulpride in patients at varying oral doses or about clinically relevant interactions with co-medication. The aim of the present investigation was to elucidate the factors, which affect amisulpride levels in schizophrenic patients. The plasma amisulpride levels of 85 patients with schizophrenia or schizoaffective disorder (mean age: 34.0+/-11.4 years; 40 women, 45 men) were assessed by high-performance liquid chromatography (HPLC) with fluorometric detection. The average daily dose of amisulpride was 772.3 mg (S.D. 346.7 mg) and the mean amisulpride plasma concentration was 424.4 ng/ml (S.D. 292.8 ng/ml). The interindividual variance of the amisulpride plasma concentration was high; furthermore, the plasma concentration increased linearly with the daily oral dose (r=0.50, p<0.001). Age and gender showed a significant effect on the dose-corrected amisulpride plasma concentrations-older patients and women had higher dose-corrected amisulpride plasma concentrations than younger patients and men. However, cigarette consumption had no effect on the amisulpride plasma concentrations. Regarding co-medication with lithium and/or clozapine, significantly higher amisulpride plasma concentrations were found as compared to monotherapy, whereas other co-medications such as benzodiazepines and various conventional antipsychotics had no effect on the amisulpride plasma concentrations. The results, the possible pathomechanisms and the clinical relevance are discussed. The findings need to be confirmed in larger patient samples and with a wider range of co-medications.     

Metabolic control in patients with schizophrenia treated with amisulpride or olanzapine

The use of certain atypical antipsychotics has been associated with metabolic disturbances. We have assessed the evolution of body weight and glycaemia during a 6-month randomized comparative trial of amisulpride and olanzapine. Three hundred and seventy-seven adult patients with schizophrenia were randomized to either amisulpride (200-800 mg/day) or olanzapine (5-20 mg/day) for 6 months. Body weight and fasting blood glucose were measured. Both treatments showed comparable antipsychotic activity. Weight gain over the study was significantly greater (P=0.0004) in the olanzapine group (3.9+/-5.3 kg) than in the amisulpride group (1.6+/-4.9 kg). Mean fasting blood glucose increased in the olanzapine group by 4.42 mg/dl to a mean maximum value (118+/-38 mg/dl). In the amisulpride group, mean glucose levels fell by 2.82 mg/dl. The difference between groups was significant at 2 (P=0.0066) and 6 months (P=0.017). One olanzapine-treated patient was diagnosed with diabetes. Metabolic changes in the amisulpride group were restricted to patients with high body mass index at inclusion. At doses that provide comparable control of psychosis, treatment with olanzapine was associated with greater increase in weight and blood glucose compared with amisulpride. This should be taken into account in assessing risk-benefit of treatment options in schizophrenia.     

Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59, P < 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73, P < 0.0001). In particular, CL/F values in children aged less than 10 years (112 +/- 82 mL/kg/h, mean +/- SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 +/- 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 +/- 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 +/- 2.2 micrograms/mL, n = 30) and those having no clinical improvement (5.2 +/- 2.2 micrograms/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.     

Therapeutic drug monitoring of the antidepressant mirtazapine and its N-demethylated metabolite in human serum

Mirtazapine is a novel antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. Because very little is known about serum concentrations in relation to clinical effects, the use of therapeutic drug monitoring is so far unclear. A rapid automated HPLC method with fluorescence detection was developed for routine quantification of mirtazapine and its demethylated metabolite N-desmethylmirtazapine in human serum. The precision of the method was suitable because the day-to-day (n = 7) coefficient of variation (CV) of mirtazapine was 9.8, 4.2, and 5.1% for concentrations of 10, 40, and 80 ng/mL, respectively, and the CV for N-desmethylmirtazapine were 11.6, 10.3, and 9.5% for 5, 20, and 40 ng/mL, respectively. The bias ranged between 0.7 and 4.2 ng/mL and between 0.9 and 2.0 ng/mL for mirtazapine and N-desmethylmirtazapine, respectively. Serum samples of 100 patients, aged between 18 and 93 years, were analyzed. There was wide interindividual variability of serum concentrations on each dose level, and the median (25th to 75th percentiles) of the mirtazapine and N-desmethylmirtazapine concentrations was 19.5 (11.0-28.7) and 9.0 (6.0-17.0) ng/mL, respectively. Women had higher dose-corrected concentrations (C/Ds, ng/mL/mg) of mirtazapine [median (25th-75th percentiles) 0.6 (0.4-0.9) vs 0.4 (0.3-0.6) and N-desmethylmirtazapine [0.4 (0.2-0.6) vs 0.2 (0.1-0.4)] than men. Patients over 60 years of age (mean age +/- SD was 72.2 +/- 7.1) had higher C/Ds of mirtazapine and N-desmethylmirtazapine [0.7 (0.4-1.2) vs 0.53 (0.4-0.8) and 0.5 (0.2-0.9) vs 0.3 (0.2-0.9), respectively] than younger patients (mean age +/- SD was 43.3. +/- 10.6). Patients with N-desmethylmirtazapine/mirtazapine ratios less than 0.4 had significantly more side effects (P < 0.05) than those having higher ratios. Comedications were assessed for drug-drug interaction, and significantly (P < 0.05) lower N-desmethylmirtazapine/mirtazapine ratios were found under concomitant medications of the antidepressant sertraline and the antipsychotic amisulpride.     

High striatal occupancy of D2-like dopamine receptors by amisulpride in the brain of patients with schizophrenia

The 'atypicality' of the antipsychotic drug, amisulpride, has been attributed to preferential extrastriatal binding. Previous investigations of striatal D2 receptor occupancy by amisulpride revealed conflicting results. The aim of this PET study was to measure the striatal occupancy by amisulpride and to correlate it with the corresponding drug plasma concentrations. Nine amisulpride-treated patients and 12 healthy volunteers serving as controls were studied with PET and [18F]desmethoxyfallypride. Occupancy values and plasma concentrations were nonlinearly fitted to an E max model. Results showed 43-85% (putamen) and 67-90% (caudate) D2-like receptor occupancy. Plasma amisulpride concentrations at the time of tracer injection, but not administered doses, were significantly nonlinearly correlated to occupancy levels (putamen: rS=0.88, p=0.0017; caudate: r S=0.78, p=0.0127). Calculated Emax was similar in both caudate and putamen, but occupancy levels were lower in caudate at lower amisulpride plasma concentrations. Calculated plasma levels to attain 60-80% receptor occupancy ranged from 119 to 474 ng/ml (caudate) and from 241 to 732 ng/ml (putamen). This reveals a broad range of plasma concentrations producing less than 80% striatal receptor occupancy. However, our data show high striatal D2-like receptor occupancies under rising plasma concentrations. Using the full range of recommended amisulpride dosage, striatal occupancies up to 90% can be measured.     

氨磺必利与利培酮治疗首发精神分裂症的随机双盲双模拟平行对照试验

目的：探讨氨磺必利与利培酮治疗精神分裂症的疗效及安全性。方法：采用随机、双盲、双模拟、平行对照试验方法,将34例符合诊断标准的首发精神分裂症患者随机分为氨磺必利组和利培酮组,每组17例。氨磺必利和利培酮的治疗剂量分别为800～1 200 mg·d~（-1）和2～6 mg·d~（-1）。疗程均为8周。于治疗前及治疗第1,2,4,8周末采用阳性和阴性症状评定量表（PANSS）评定疗效,采用治疗中出现的症状量表（TESS）及实验室检查来评价安全性。结果：治疗后第2,4,8周末,两组PANSS总分较治疗前均显著降低（P〈0.05）;氨磺必利组和利培酮组总有效率分别为88.2%和82.4%,差异无统计学意义（P〉0.05）。两组不良反应发生率比较差异亦无统计学意义（P〉0.05）。结论：氨磺必利和利培酮对治疗精神分裂症的疗效相当,不良反应轻,值得临床应用。     

A review of the pharmacokinetics,tolerability and pharmacodynamics of amisulpride in healthy volunteers

Amisulpride binds selectively to dopamine D(2) and D(3) receptors in the limbic system. Low doses of amisulpride preferentially block presynaptic D(2)/D(3)-dopamine autoreceptors, thereby enhancing dopaminergic transmission, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. Amisulpride is clinically effective on the negative symptoms of acute schizophrenia exacerbations at low dosages (50-300 mg/day), and also on the positive symptoms of the disease at high dosages (400-800 mg/day). Nineteen clinical studies involving 358 volunteers have investigated the pharmacokinetics, pharmacodynamics and tolerability of amisulpride. Amisulpride shows linear pharmacokinetics, a bioavailability of 48%, low protein binding (17%) and an elimination half-life of approximately 12 h. It is predominantly eliminated in the urine as the parent compound. It exhibits no significant detrimental effects in psychometric or memory tests up to the dose of 400 mg/day, inducing only mild impairment at high doses, whereas EEG data suggest an alertness-enhancing effect at low doses (相似文献   

Effects of Dopamine D2/D3 Blockade on Human Sensory and Sensorimotor Gating in Initially Antipsychotic-Naive,First-Episode Schizophrenia Patients

It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits.     

Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Amisulpride Study Group

Amisulpride is an atypical antipsychotic with selective affinity for dopamine D2/3 receptors. In this long-term, open, randomised, multicentre trial, patients with chronic or subchronic schizophrenia received amisulpride (n =370) or haloperidol (n = 118) for 12 months. Dosage regimens were flexible (amisulpride 200-800 mg/day, haloperidol 5-20 mg/day). Improvement in mean Brief Psychiatric Rating Scale total score was significantly greater for amisulpride than haloperidol (17.0 versus 12.8, P = 0.01). Positive symptoms (Positive and Negative Syndrome Scale [PANSS] positive) improved in a similar way in each group but amisulpride caused a significantly better improvement in negative symptoms (PANSS negative) (7.1 versus 3.7, P < 0.0001). Improvements in Global Assessment of Functioning (GAF) and Quality of Life Scale (QLS) scores were also significantly greater in the amisulpride group (GAF -20.1 versus -13.6, P = 0.001; QLS -0.64 versus -0.30, P = 0.02). Adverse events were mainly psychiatric in nature, and occurred with similar frequency in each group (amisulpride 254/370, 69%; haloperidol 82/118, 70%). Extrapyramidal symptoms were more frequent for haloperidol (48/118, 41% versus 96/370, 26% for amisulpride), leading to a greater requirement for antiparkinsonian medication (haloperidol 66/118, 56% versus amisulpride 118/370, 32%). Haloperidol significantly aggravated parkinsonism, akathisia and involuntary movement compared to amisulpride. The overall incidence of endocrine events was comparable between groups (4% for amisulpride, 3% for haloperidol). Maintenance of efficacy was comparable in both treatment groups; 59% of amisulpride patients and 55% of haloperidol patients improved after 1 month of therapy remained improved throughout the study period. Amisulpride is effective following flexible long-term administration and significantly improves social functioning and quality of life.     

Amisulpride improves depressive symptoms in acute exacerbations of schizophrenia: comparison with haloperidol and risperidone.

The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess affective symptoms in three studies (n = 612) comparing amisulpride (400-800 mg/day, n = 339) with haloperidol (15-20 mg/day, n = 160) and risperidone (8 mg/day, n = 113) in the treatment of acute exacerbations of schizophrenia. At endpoint, the mean improvement in the anxiety/depression subscore showed a significant (P = 0.011) difference in favour of amisulpride (5.6+/-6.1) compared with haloperidol (4.4+/-5.5) and risperidone (3.7+/-4.7). Amisulpride provided a significantly greater improvement compared both to haloperidol and risperidone in more severely depressed patients (BPRS anxiety/depression subscore > or = 16 at baseline, P = 0.001). This significant advantage in favour of amisulpride is seen from the 2nd week of treatment.     

Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study

The beneficial effect of sulpiride augmentation of clozapine therapy for treatment-resistant schizophrenia patients is enhanced by its antisalivatory effect on clozapine-induced hypersalivation (CIH). Amisulpride, similar to sulpiride, is a substitute benzamide derivative with higher selective binding to the D2/D3 dopamine receptor. We hypothesized that add-on amisulpride would also be beneficial in controlling CIH. In a randomized, double-blind, placebo-controlled cross-over study, 20 clozapine-treated schizophrenia (DSM-IV criteria) inpatients with CIH were randomly initially assigned to add-on amisulpride (nine patients; 400 mg/day up-titrated from 100 mg/day over 1 week) or placebo (11 patients). Primary outcome was change in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Other measures included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression scale (CGI) and Simpson-Angus Scale (SAS). Mean NHRS indices were considerably lower with amisulpride (1.79 +/- 1.25) than with placebo (2.63 +/- 1.33) [F(1,38) = 5.36, P < 0.05]. With amisulpride treatment, there was a significant improvement on the negative symptoms subscale of the PANSS [F(3,57) = 3.76, P < 0.05], but not on the SAS, CGI or other subscales of the PANSS (all F < 1). Short-term amisulpride augmentation has a strong ameliorating effect on CIH. A long-term, large-scale study with a broader dose range is warranted to evaluate the stability of this effect across time.     

Spotlight on amisulpride in schizophrenia

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D(2)/D(3) autoreceptors. At higher doses, amisulpride antagonises postsynaptic D(2) and D(3) receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or = 300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. Conclusion: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Effect of the amisulpride isomers on rat prolactinemia

The effects on rat serum prolactin level of the two isomers constituting the racemic form of amisulpride were compared. (S-)-amisulpride induced hyperprolactinemia at lower doses (ED(50) = 0.09 +/- 0.01 mg/kg) than racemic- (ED(50) = 0.24 +/- 0.03 mg/kg) and (R+)-amisulpride (ED(50) = 4.13 +/- 0.05 mg/kg), in accord with their affinities for pituitary dopamine D(2) receptor (K(i) = 3.8 +/- 0.2, 6.4 +/- 0.2 and 143.3 +/- 2.3 nM, respectively). At doses twice the ED(50), (S-)-amisulpride produced a maximal increase in prolactin level similar to that of the racemic form (403 +/- 21% and 425 +/- 15%, respectively), but higher than that of (R+)-amisulpride (198 +/- 8%). These results suggest that the hyperprolactinemia induced by the racemic-amisulpride is mostly due to its (S-)-isomer.     

Amisulpride: a review of its use in the management of schizophrenia

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.     

Amisulpride: a review of its use in the management of schizophrenia.

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisupride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or =300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. CONCLUSION: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia

Amisulpride, a substituted benzamide with high affinity for dopamine D2 and D3 receptors only, has been reported to have therapeutic effects on both negative and positive schizophrenic symptoms, although at distinct dose ranges (50-300 mg/day vs. 400-1,200 mg/day). The purpose of this study was to investigate the binding of amisulpride to extrastriatal (i.e., thalamus and temporal cortex) and striatal D2 dopamine receptors with respect to plasma amisulpride determinations. Ten patients with schizophrenia treated with amisulpride over a wide range of doses (25-1,200 mg/day) were studied. Positron emission tomography images were acquired by using 76Br-FLB-457, a highly specific antagonist of the D2 and D3 dopamine receptors. Binding indexes (BI) in the regions studied were estimated with reference to values from six healthy subjects. A curvilinear relationship was demonstrated between plasma concentration of amisulpride and the BI in extrastriatal regions. The BI also varied as a function of plasma concentration in striatum. Furthermore, the data provide evidence for different binding profiles: low plasma concentrations (28-92 ng/mL) induced marked extrastriatal binding and low striatal binding, whereas higher plasma concentrations (>153 ng/mL) induced marked binding both in extrastriatal and striatal regions. Dose-dependent differential binding profiles of amisulpride to D2 receptors in extrastriatal and striatal regions were demonstrated, and two therapeutic ranges of plasma concentrations for negative and positive schizophrenic symptoms, respectively, are suggested.     

Therapeutic monitoring of new antipsychotic drugs

Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350-600 ng/mL), risperidone (20-60 ng/mL), and olanzapine (20-80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.     

Acetazolamide blood concentrations are excessive in the elderly: propensity for acidosis and relationship to renal function

Elderly glaucoma patients are often treated with acetazolamide, a carbonic anhydrase inhibitor with clearance dependent on renal function. A high incidence of metabolic acidosis and other adverse effects have been noted among these patients but the reasons for this have not been explained. We hypothesized that commonly used doses of acetazolamide among the elderly result in excessive blood concentrations and that these concentrations are related to acid-base disturbances. We measured steady-state acetazolamide levels in plasma, plasma ultrafiltrate (unbound), and erythrocytes among 12 elderly subjects (79.2 +/- 7.6 years old). Mean plasma (18.9 +/- 10.9 micrograms/mL) and ultrafiltrate concentrations (1.0 +/- 0.7 microgram/mL) exceeded the therapeutic range (plasma 5-10 micrograms/mL; ultrafiltrate 0.25-0.50 microgram/mL) for glaucoma control by two fold and were elevated in 75% of subjects. Plasma and ultrafiltrate acetazolamide levels significantly correlated with the dose adjusted for creatinine clearance (r = 0.91, P less than 0.001; r = 0.89, P less than 0.001, respectively). Acidotic subjects (serum total carbon dioxide less than or equal to 22 mEq/L) tended to have higher plasma, ultrafiltrate, and erythrocyte acetazolamide levels compared with nonacidotic subjects. Serum total carbon dioxide levels were significantly correlated with erythrocyte acetazolamide concentrations (r = -0.75, P = 0.03). The ratio of erythrocyte acetazolamide concentration to creatinine clearance separated acidotic from nonacidotic subjects (P less than 0.01). These findings suggest that some of the adverse effects of acetazolamide can be avoided by reducing the dose to compensate for age-related reductions in renal drug clearance.     

Effects of olanzapine on lipid abnormalities in elderly psychotic patients

INTRODUCTION: Recently concern regarding the cause or worsening of diabetes mellitus by some of the second-generation antipsychotics and their adverse affects on lipid metabolism has caused growing concern amongst physicians and patients. This study aims to assess these effects in elderly patients with schizophrenia. METHODS: In a prospective 6-month follow-up study of elderly inpatients experiencing an acute psychotic exacerbation and exposed to olanzapine for the first time, patients underwent physical and psychiatric assessments including: routine laboratory tests (including serum cholesterol and triglycerides levels), and bodyweight and clinical rating scale measurement. All tests and evaluations were performed at baseline and at the end of study. RESULTS: Twenty-one elderly patients with schizophrenia (15 women and six men) mean age 71.7 +/- 8.2 years were included. All were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (4th edition) as patients with schizophrenia or schizoaffective disorder. Mean duration of olanzapine treatment was 289 days (SD +/- 139) and the mean olanzapine dosage at the end of the study was 12.9 mg/day. At the end of the study, no significant change from baseline serum lipid levels were found for triglycerides (paired differences = -12.8 [SD +/- 38.5], 95% CI -30.3 to +4.7, t = -1.5, df = 20, p = 0.143) or cholesterol (paired differences = -9.0 [SD +/- 43.5], 95% CI = -28.8 to +10.8, t = -0.95, df = 20, p = 0.355). CONCLUSION: The association between olanzapine exposure and lipid abnormalities may not hold true for older patients. Larger studies with elderly patients are needed to support the present report.     

Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

RATIONALE: Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established. OBJECTIVE: We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response. METHODS: Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. RESULTS: Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations. CONCLUSIONS: These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.