Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients

BACKGROUND: Olanzapine, a thienobenzodiazepine, is one of the relatively new atypical antipsychotic drugs. The lowest threshold of effective olanzapine plasma levels in inpatient treatment is assumed to be 9 ng/ml. Very little is known about the plasma concentration in patients at various oral doses of olanzapine or about the clinically relevant interactions with co-medications. METHODS: In 71 schizophrenic patients (age 32.6 +/- 12.1, range 18-63 years; 31 women, 40 men), plasma olanzapine levels were assessed in 377 tests by high-performance liquid chromatography (HPLC) with electrochemical detection. Fifty-six of these plasma levels were assessed while patients were receiving olanzapine as monotherapy; otherwise, the plasma levels were assessed with the patients receiving various co-medications. RESULTS: The mean daily oral dose of olanzapine was 17.5 mg (SD = 7.0, range 5-40 mg), and the mean olanzapine plasma concentration was 54.2 ng/ml (SD 37.8 ng/ml, range 1.2-208 ng/ml). The plasma concentration of olanzapine increased linearly with the daily oral dose (r = 0.64, p < 0.001). A multiple variance analysis considering age and sex as covariables showed a significant difference in the dose-corrected plasma levels of olanzapine among 40 smokers and 31 non-smokers; age and sex did not affect the dose-corrected plasma levels. However, women received a significantly lower daily dose of olanzapine under routine clinical study conditions. No differences could be detected among the dose-corrected plasma concentration of those patients who were taken off olanzapine because they did not respond (n = 14) or because of side effects (n = 5) and those who were discharged while still on olanzapine. Under the co-medication with fluvoxamine, significantly higher dose-corrected olanzapine plasma concentrations were found than with olanzapine monotherapy, whereas significantly lower dose-corrected olanzapine plasma concentrations were detected under lithium and trimipramine co-medication. Under co-medication with amitriptyline, benperidol, carbamazepine, flupentixol, and lorazepam, the dose-corrected olanzapine plasma concentrations were no different than the plasma levels under olanzapine monotherapy. CONCLUSIONS: The relevance of therapeutic drug monitoring is emphasized with respect to the data presented and to the literature. Future studies should examine, in particular, the effects of a wider range of co-medications in a larger patient sample.     

Major adverse reactions during desipramine treatment: relationship to plasma drug concentrations, concomitant antipsychotic treatment, and patient characteristics

Major adverse reactions interrupting drug therapy during treatment of 84 patients with desipramine hydrochloride were studied to determine their relationship to desipramine plasma concentrations and other clinical variables. The frequency of adverse reactions was higher in patients over 60 years old (39%), and in patients also receiving antipsychotic medications (32%), but low in patients under 60 years old (7%). Desipramine plasma concentrations in patients having side effects did not differ significantly from those in patients without side effects. Steady state desipramine plasma concentrations did not increase with age. Symptomatic orthostatic hypotension, the most common side effect encountered, occurred early in treatment at low desipramine plasma concentrations. Other side effects, usually described as anticholinergic, occurred exclusively in the 34 patients receiving both desipramine and antipsychotic drugs. The concentration of 2-hydroxy-desipramine, the total concentration of 2-hydroxy-desipramine and desipramine, and the ratio of 2-hydroxy-desipramine to desipramine were not higher in 11 patients having side effects than in a comparison group without side effects.     

Increased plasma neurotensin concentrations in patients with Parkinson's disease

Plasma neurotensin (NT) was measured by radioimmunoassay in propanol extracted and unextracted plasma from 16 parkinsonian patients (four before treatment) and 16 age and sex matched controls. Mean plasma NT concentrations were consistently higher in parkinsonian patients than in controls and higher in the four untreated patients than in levodopa treated patients suggesting that plasma NT measurement may represent an easy detectable additional index in diagnosing parkinsonism and provides a novel approach to research in this field.     

Sex-related differences in nortriptyline-induced side-effects among depressed patients.

1. Men and women may differ in their pharmacokinetic responses to tricyclic antidepressants (TCAs), in a number of autonomic indices, and in various adrenergic receptor mediated responses. Emerging evidence also suggests that women may have a lower rate of serotonin synthesis in brain and a greater sensitivity to the depressant effects of tryptophan depletion, relative to men. However, sex-related differences in TCA-induced side-effects, including increases in heart rate (HR), dry mouth, constipation, and difficulty urinating, has not been systematically investigated. 2. The authors examined potential sex-related differences in the pattern of side-effects during treatment with nortriptyline (NT), a TCA that is still widely used. Seventy-eight healthy outpatients who met Research Diagnostic Criteria and DSM-III-R criteria for major depression participated in a double-blind, randomized parallel trial of NT versus placebo. 3. Each subject was acutely challenged with either placebo or 50 mg NT prior to and after a 6-week treatment with NT. NT doses were adjusted weekly to maintain therapeutic plasma levels. Patients were assessed at multiple time points to detect the presence of NT-induced side-effects. 4. The initial, single (50 mg) dose of NT significantly increased supine HR. Six-week treatment with NT was found to significantly increase supine and sitting HRs, irrespective of sex. In rechallenge with the single NT dose, there were no significant effects on HR. 5. When sex-related differences were examined, HR increases were greater in men than women during weeks 4 through 6 of the NT treatment, although no sex-related differences were present in plasma NT levels or metabolites. In addition, there was a significant NT to placebo difference in self-rated dry mouth for women during all 6-weeks of treatment, whereas men showed a significant NT-placebo difference during weeks 3 and 5. 6. The results suggest the presence of sex-related differences in elevated supine HR response during the course of 6-week NT treatment. Depressed men may be more susceptible to NT-induced increases in supine HR than women.     

Ratio of plasma fluoxetine to norfluoxetine concentrations and associated sedation.

BACKGROUND: Sedation is an often unanticipated but clinically significant side effect in some patients treated with fluoxetine. To date, no clinical or pharmacokinetic factors have been identified in association with sedation in fluoxetine-treated patients. We hypothesized that patients experiencing sedation might have elevated plasma concentrations of fluoxetine and/or norfluoxetine compared with patients without sedation. METHOD: Plasma samples from eight patients reporting new-onset sedation following initiation of treatment with fluoxetine and from 14 consecutive patients also receiving fluoxetine but who experienced no sedation were analyzed for fluoxetine and norfluoxetine concentrations. RESULTS: Patients in the two groups did not differ significantly in age, sex distribution, diagnoses, mean dose or duration of fluoxetine treatment, or mean combined plasma concentrations of fluoxetine and norfluoxetine. However, the plasma ratio of fluoxetine to norfluoxetine was less than 1.0 in all patients reporting sedation and greater than 1.0 in all patients without sedation. Also, there was a significant difference between the mean +/- SD ratio of fluoxetine-to-norfluoxetine plasma concentrations in the group reporting sedation (0.6 +/- 0.1) and the group without sedation (1.7 +/- 0.8). CONCLUSION: The results of this study suggest an association between sedation and increased plasma concentrations of norfluoxetine compared with fluoxetine. Individuals reporting sedation may metabolize the parent drug differently than patients who do not experience sedation, leading to a relative increase in the proportion of the active metabolite, norfluoxetine.     

Risperidone plasma levels,clinical response and side–effects

INTRODUCTION: Assessment of the relation between oral risperidone dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Inter-individual differences in the liver cytochrome P450 system, especially in the CYP2D6 subsystem, which account for a significant portion of risperidone metabolism, may also influence plasma drug levels and alter clinical response parameters. We thus prospectively investigated risperidone serum concentrations in relation to clinical efficacy and side-effects and genotyped major CYP2D6 polymorphisms to determine their effect upon these parameters. METHODS: Neuroleptic monotherapy with risperidone was administered to schizophrenia patients in a 6-week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of risperidone and 9-OH-risperidone were carried out. In addition, major CYP2D6 polymorphisms including alleles *4, *6 and *14 were genotyped. RESULTS: Eighty-two patients were recruited. Mean oral dose of risperidone was 4.3 +/- 0.9 mg. Mean plasma level of both risperidone and 9-OH-risperidone together ("active moiety") was 41.6 +/- 26.6 ng/ml. Significant improvements in PANSS scales and the various subscales ensued. There was a positive linear correlation between active moiety plasma levels and dose (r = 0.291, p = 0.015) and between risperidone and 9-OH-risperidone levels (r = 0.262; p = 0.016). Nonresponders to pharmacotherapy (PANSS-Improvement < 30%) showed significantly higher active moiety plasma levels (49.9 +/- 30.7 ng/ml) than responders (38.2 +/- 17.0 ng/ml; p = 0.045) without significantly higher oral doses (p = 0.601). Patients with longer illness duration (> or = 3 years) had significantly higher plasma drug levels than those with a shorter course (< 3 years; p = 0.039). Extrapyramidal side effects (EPS) and plasma levels were not correlated (r = 0.028; p = 0.843), but higher plasma levels at week 2 predicted an incidence for EPS (p < 0.050). Accordingly, patients initially receiving higher oral doses of risperidone were significantly more likely to respond with EPS in the trial course. Eight patients (9.8%) were heterozygous carriers of the CYP2D6 allele *4. CYP2D6 polymorphisms did not predict clinical response, but predicted a tendential increase in the plasma risperidone to 9-OH-risperidone ratio (0.5 +/- 0.6 vs. 1.9 +/- 1.8; p = 0.120). DISCUSSION: The major finding was that responders to risperidone treatment had significantly lower blood levels of risperidone and 9-OH risperidone than patients who did not respond to the treatment despite administration of similar oral doses. The observed CYP2D6 polymorphisms did not contribute to altered clinical efficacy, but affected risperidone to 9-OH-risperidone ratios. Increased plasma levels of the active moiety in patients with longer illness may represent general aging effects. Conversely, the observed higher plasma levels in nonresponders may derive from unaccounted genetic metabolism abnormalities or Phase II metabolism disturbances. Patients initially receiving higher oral risperidone doses were more likely to respond with extrapyramidal side effects which reaffirms the need for careful titration. The high inter-individual variability in risperidone and 9-OH-risperidone metabolization and the relationship between clinical outcome and plasma levels warrants regular plasma level monitoring of both compounds to assess for the clinically relevant active moiety.     

Loss of the cortisol response to naltrexone in Alzheimer's disease

The administration of a single dose of the opiate antagonist naltrexone (NT) was accompanied by significant elevations in plasma cortisol in normal elderly subjects; in contrast, the cortisol response to NT was absent in individuals of comparable age with Alzheimer's disease (AD). The differential effect of AD on the cortisol response was not accompanied by a significant group difference in plasma prolactin in response to NT administration. Furthermore, this differential cortisol response to NT was not associated with any evident differences in age, sex ratio, plasma levels of naltrexone or its major metabolite beta-naltrexol, or with differences in measures of nonspecific stress, such as plasma free MHPG, pulse, or blood pressure, between the two groups. The absence of the well-characterized cortisol response to NT in AD, together with other reports of abnormal responses to other pharmacological challenges, suggests that neuroendocrine abnormalities might be an important concomitant and possibly a central contributor to the pathophysiology of Alzheimer's disease.     

Zimeldine to geriatric patients in once daily dosage. A pharmacokinetic and clinical study

The therapeutic efficacy, tolerability and pharmacokinetics of zimeldine in elderly depressed patients were evaluated after administration of different doses of the drug in once daily evening doses. The doses of zimeldine were 100 mg during the first 2 weeks, 150 mg during the next 2 weeks and 200 mg during the last 2 weeks. Nine of the 11 patients (mean age 78 years) included in the study completed the 6-week treatment period, and all nine improved according to the Hamilton depression rating scale. The drug was well tolerated and the side effects were few and mild. No influence of clinical importance was noted in haematology, liver and kidney functions, EEG, blood pressure or pulse rate. Steady-state plasma concentrations of zimeldine, and its active metabolite norzimeldine, were achieved in most cases after 1 week of treatment in each dose regimen. The plasma concentrations increased linearly with the increase in dose. The maximal interindividual variations in plasma concentrations were 8-fold for zimeldine and 3-fold for norzimeldine . The plasma levels of both zimeldine and norzimeldine were higher in the elderly than reported earlier in younger patients. The ratio of norzimeldine/zimeldine concentrations was reduced in the elderly, indicating a reduction of the metabolic capacity. The results suggest that zimeldine can be administered in a once daily dosage regimen to elderly patients, but they should be given a lower dose than younger patients.     

Neurotensin-like immunoreactivity in cerebrospinal fluid of patients with schizophrenia, depression, anorexia nervosa-bulimia, and premenstrual syndrome

Neurotensin (NT) concentrations in cerebrospinal fluid (CSF) were measured by a sensitive and specific radioimmunoassay in psychiatric patients and age- and sex-matched normal controls. No increase in CSF NT concentrations was observed after antipsychotic drug treatment. CSF NT concentrations were significantly lower in one group of schizophrenic subjects. NT concentrations were unaltered in patients with depression, anorexia/bulimia, or premenstrual syndrome, and no rostral-caudal gradient for NT in CSF was evident. NT concentrations were not related to age or sex, and probenecid treatment did not alter CSF NT concentrations. Finally CSF NT concentrations were unaltered in paranoid schizophrenic subjects. These findings confirm and extend previous studies of CSF NT that showed certain patients with schizophrenia, nonparanoid type, have reduced CSF concentrations of this tridecapeptide.     

Effects of CI-943, a potential antipsychotic drug, and haloperidol on regional brain neurotensin concentrations.

Treatment with efficacious antipsychotic drugs such as haloperidol increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate nucleus of the rat. These increases in NT concentrations may be associated with the therapeutic and/or side effects of these drugs. CI-943, a novel compound without appreciable affinity for dopamine-binding sites, produces behavioral effects in animals, which suggest that it may possess antipsychotic activity. This study evaluated the effects of subchronic treatment (3 weeks) with CI-943 or haloperidol on regional brain NT concentrations in rats. Haloperidol treatment (1 mg/kg) produced significant increases in the concentrations of NT in the nucleus accumbens and caudate nucleus but not in the other brain regions studied. Like haloperidol, CI-943 (40 mg/kg) increased NT concentrations in the nucleus accumbens and caudate but differed in that CI-943 produced significantly greater increases in NT concentration in the caudate than haloperidol and also increased NT content in the substantia nigra/ventral tegmental area and hypothalamus. The regional specificity of the NT alterations produced by chronic treatment with CI-943, a nondopamine receptor ligand, was similar to that previously reported after treatment with multiple doses of methamphetamine.     

Ontogeny of the effect of antipsychotic drug treatment on neurotensin concentrations in the rat brain

It has been well documented that treatment with haloperidol and other typical antipsychotic drugs increase neurotensin (NT) concentrations in the nucleus accumbens and caudate nucleus in adult rats. The NT neuronal system has been found to undergo distinct age-related changes in the rat brain, and therefore, it is of interest to examine the ontogeny of the effects of antipsychotic drug treatment on NT concentrations. In order to determine when, or if, antipsychotic drug treatment has an effect on NT-containing neurons in the developing rat, rat pups received a single dose of haloperidol (2.0 mg/kg, s.c.) or vehicle at 9, 14, or 20 days after birth. Regional brain NT concentrations were then measured using a sensitive and specific radioimmunoassay. Treatment with haloperidol had no effect on NT concentrations in any brain region in 10-day-old rat pups. At 15 days of age, haloperidol significantly increased NT concentrations in the caudate nucleus (120% of control, P < 0.05). At 21 days of age, haloperidol increased NT concentrations in the caudate nucleus (193% of control, P < 0.001) and nucleus accumbens (126% of control, P < 0.005) similar to that seen in adult animals. There were no statistically significant gender-related differences found in any age or treatment group studied. These findings indicate that there is a specific time point during postnatal development when rat brain NT systems become responsive to antipsychotic drug administration. © 1995 Wiley-Liss, Inc.     

Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome

OBJECTIVE: Clozapine is a unique atypical antipsychotic with superior efficacy in treatment-resistant schizophrenia. Plasma concentration of clozapine and its major metabolite N-desmethylclozapine (NDMC) as well as the ratio of NDMC to clozapine have been reported to be predictors of clozapine response. Here we evaluate these as well as other measures in an effort to find predictors of response to clozapine in our early-onset treatment-refractory population. METHOD: Fifty-four children and adolescents participated in double-blind (n = 22) or open-label (n = 32) clozapine trials. Clinical evaluations took place at baseline, week 6 on clozapine, and at 2- to 6-year follow-up. The data were analyzed in relation to demographics, age at onset, IQ, clozapine dose, and plasma concentrations of prolactin, clozapine, NDMC, and NDMC/clozapine ratio. Stepwise regression and correlation analyses were performed to find predictors of treatment response. RESULTS: Clinical improvement after 6 weeks of clozapine treatment, as measured by the percentage of improvement on the Brief Psychiatric Rating Scale and the Scale for the Assessment of Positive Symptoms, was strongly associated with the NDMC/clozapine ratio at the 6-week time point (Pearson correlation coefficient: r = 0.41; p < .01 for Brief Psychiatric Rating Scale and r = 0.43; p < .01 for Scale for the Assessment of Positive Symptoms). Although the rate of side effects was higher than that typically found in the adult population, it did not appear to be related to clozapine dose, clozapine or NDMC plasma concentrations, or NDMC/clozapine ratio. Outcome at long-term follow-up, as measured by Children's Global Assessment Scale, was associated with lesser illness severity at baseline and with greater improvement during the initial 6 weeks of clozapine treatment. CONCLUSIONS: The NDMC/clozapine ratio may be a valuable predictor of response to clozapine and may suggest new approaches to clozapine treatment.     

Age and gender effects on olanzapine and risperidone plasma concentrations in children and adolescents

BACKGROUND: Risperidone and olanzapine are second-generation antipsychotics that are increasingly used in child and adolescent psychiatry. So far, little is known about plasma concentrations and concentration-to-dose (C/D) ratios of these agents in children and adolescents compared to adults. METHOD: This study investigated whether age and gender influence risperidone and olanzapine plasma concentration by determining risperidone and olanzapine plasma levels by tandem mass spectrometry in 162 Caucasian patients (98 risperidone and 64 olanzapine). RESULTS: For risperidone and 9-hydroxyrisperidone, the C(total)/D ratio was almost identical in both age groups (10-18 and 19-45 years, respectively). In the younger age group, females exhibited significantly higher total plasma levels than males while receiving similar doses of risperidone. For olanzapine, in adolescents significantly higher C/D ratios were detected by an average of 43% (after adjustment for weight: 34%) compared to adults. CONCLUSION: This study demonstrates an age effect for olanzapine but not for risperidone resulting in higher olanzapine plasma levels in younger patients. For risperidone, we found a gender effect as female adolescent patients had significantly higher risperidone plasma concentrations than male adolescent patients. Future prospective studies are necessary to clarify whether the prescribed dosage should be different in young and older patients.     

Elevated plasma concentrations of homocysteine in antiepileptic drug treatment

PURPOSE: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nutritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations. METHODS: A total of 51 consecutive outpatients of our epilepsy clinic receiving stable, individually adjusted AED treatment and 51 sex- and age-matched controls were enrolled in the study. Concentrations of total homocysteine and vitamin B6 were measured in plasma; vitamin B12 and folate were measured in the serum of fasted subjects. RESULTS: Patients and controls differed significantly in concentrations of folate ( 13.5+/-1.0 vs. 17.4+/-0.8 nM and vitamin B6 (39.7+/-3.4 vs. 66.2+/-7.5 nM), whereas serum concentrations of vitamin B12 were similar. The homocysteine plasma concentration was significantly increased to 14.7+/-3.0 microM in patients compared with controls (9.5+/-0.5 microM; p < 0.05, Wilcoxon rank-sum test). The number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls. The same result was obtained if only patients with CBZ monotherapy were included. Patients with increased homocysteine plasma concentrations had lower folate concentrations. CONCLUSIONS: These data support the hypothesis that prolonged AED treatment may increase plasma concentrations of homocysteine, although the alternative explanation that increased homocysteine plasma concentrations are associated with the disease and not the treatment cannot be completely excluded at the moment.     

Usefulness of plasma haloperidol levels for monitoring clinical efficacy and side effects in Alzheimer patients with psychosis and behavioral dyscontrol.

OBJECTIVE: This study investigated whether measurement of plasma levels may be useful in monitoring clinical efficacy and side effects during oral haloperidol (HL) treatment of psychosis and behavioral dyscontrol in patients with Alzheimer disease (AD). METHODS: After a single-blind placebo period of 1 week, 71 outpatients with AD were randomized to a 6-week, double-blind, placebo-controlled trial of HL 2 mg-3 mg/day (standard dose), HL 0.5 mg-0.75 mg/day (low dose), or placebo, with plasma levels for HL drawn at the end of 6 weeks. RESULTS: Of the 40 patients who received active HL for 6 weeks, 35 had plasma levels drawn. Plasma levels were all below the lower limit of the postulated therapeutic range in schizophrenia. Nonetheless, HL plasma level significantly correlated with clinical efficacy as measured by reduction in Brief Psychiatric Rating Scale Total score, Psychosis factor, and Hostile-Suspiciousness factor, the Behavioral Syndromes Scale for Dementia Psychomotor Agitation scale, and with the severity of extrapyramidal side effects (EPS). Oral dose did not significantly correlate with any of these efficacy or side-effect measures. Plasma levels significantly correlated with HL dose. When both HL dose and HL plasma level were included as independent variables in linear-regression analyses, only HL plasma level was a significant predictor of efficacy and EPS. CONCLUSION: Measurement of HL plasma levels may have potential usefulness as an adjunct in monitoring treatment response to oral HL in AD patients with psychosis or disruptive behavior.     

Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin

OBJECTIVE: The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers. BACKGROUND: LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process. DESIGN/METHOD: As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl(o)), where LTG Cl(o) was estimated as the dose/concentration ratio. RESULTS: Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl(o) determined prior to withdrawal of the inducers was significantly greater in patients (n=28) on LTG+PHT (160% increase) than in those (n=48) receiving LTG+CBZ (62% increase): 1.77+/-0.77 vs. 1.06+/-0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl(o) occurred only when CBZ plasma concentrations reached approximately 2 microg/ml or PHT plasma concentrations reached zero. CONCLUSIONS: Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.     

Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice

OBJECTIVE: The aim of this study was to evaluate the benefit of mirtazapine plasma concentration monitoring in a typical clinical setting. METHODS: The relationship between mirtazapine plasma concentration, dose, response, and side effects was studied in 65 inpatients presenting with a depressive episode according to ICD-10. Plasma concentrations, the 17-item Hamilton Depression Rating (HAMD), and the UKU side effect rating were performed weekly. A subgroup of 45 patients was evaluated for a concentration-response relationship. RESULTS: We found a low positive correlation between plasma concentration and dose. A low negative correlation between plasma concentration and increased duration of sleep was noted in the first week of mirtazapine treatment, but not during the entire observation time. Responders to mirtazapine treatment presented with higher plasma concentrations than non-responders, revealing a threshold concentration of 30 ng/mL. CONCLUSION: The mirtazapine dose is a weak predictor of mirtazapine plasma concentrations. Plasma concentration measurements may therefore be useful to adjust mirtazapine doses in non-responders with plasma concentrations below 30 ng/mL. Sedative effects appear temporary and require no plasma concentration control when standard doses are administered.     

Alprazolam plasma concentrations and treatment response in panic disorder and agoraphobia.

OBJECTIVE: The authors' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia. METHOD: Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week, fixed-dose, double-blind, placebo-controlled, dose-response study of 2 mg/day or 6 mg/day of alprazolam. Assessments were made of panic attacks, avoidance behavior, generalized anxiety, and global response. Blood samples were collected throughout the study and analyzed for alprazolam and other benzodiazepines. RESULTS: Patient compliance with the protocol was judged to be good on the basis of plasma concentrations. According to logistic regression analysis, the relationships between plasma alprazolam concentration and response, as reflected by number of panic attacks reported, phobia ratings, physicians' and patients' ratings of global improvement, and the emergence of side effects, were significant. However, there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms. CONCLUSIONS: The authors conclude that plasma concentration of alprazolam is related to treatment response, particularly in panic attacks. The alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals, highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects.     

Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels

OBJECTIVE: The atypical antipsychotic risperidone significantly raises plasma prolactin levels in patients, but clozapine, olanzapine, and quetiapine do not. The differences in neuroendocrine response may be connected with the metabolism of the medications. The authors examined the contributory role of risperidone's active metabolite 9-hydroxy-risperidone by measuring plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin. METHOD: Blood samples taken from 25 patients with psychotic disorders following 6 weeks of treatment with risperidone (mean dose=3 mg/day) were examined. Mean plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin were 4.6, 19.4, and 49.3 ng/ml, respectively. RESULTS: The oral dose of risperidone correlated significantly with plasma concentrations of risperidone, 9-hydroxy-risperidone, active moiety, and prolactin. The plasma concentration of 9-hydroxy-risperidone, but not of risperidone, correlated significantly with increases in plasma prolactin. CONCLUSIONS: These data suggest that the 9-hydroxy metabolite plays a predominant role in risperidone's effect on prolactin release.     

Elevated plasma γ-aminobutyrate/glutamate ratio and responses to risperidone antipsychotic treatment in schizophrenia

Background

γ-aminobutyrate (GABA) and Glutamate (Glu) are respectively two major inhibitory and excitatory neurotransmitters in the central nervous system and recent theories propose that both of their signaling complexes are compromised in patients with schizophrenia.

Methods

The changes in plasma GABA, Glu and GABA/Glu ratio in schizophrenia have been studied and may be potential clinical markers. Here, we examined if plasma GABA, Glu and GABA/Glu ratio are altered in 32 schizophrenics, including a comprehensive investigation of their involvements with clinical course of a 6-week risperidone antipsychotic treatment.

Results

Plasma levels of GABA and Glu were significantly lower in patients than in controls, while plasma GABA/Glu ratio was significantly elevated. During treatment, a non-significant further decrease of plasma GABA, a significant increase of plasma Glu and a significant reduction of plasma GABA/Glu ratio were observed. The ratio returned to the control level at week 6 even though concentrations of GABA and Glu were still distant from normal. After the Bonferroni correction, partial correlation analyses showed that plasma GABA and GABA/Glu ratio were positively correlated with the dose of risperidone and plasma concentration of 9-hydroxyrisperidone. The reduction of plasma GABA/Glu ratio was positively correlated with the improvement of activation symptom cluster.

Conclusions

The elevated plasma GABA/Glu ratio reinforces the idea of an abnormal GABA-Glu interaction in schizophrenia. The ratio may be a good peripheral state-like marker in schizophrenia research.