Fluphenazine Plasma Levels Research Articles

Microneedle array patches for sustained delivery of fluphenazine: A micron scale approach for the management of schizophrenia

Schizophrenia is a severe chronic mental illness characterised by impaired emotional and cognitive functioning. To treat this condition, antipsychotics are available in limited dosage forms, mainly oral and injectable formulations. Although injectable antipsychotics were designed to enhance adherence, they are invasive, painful and require a healthcare professional to be administered. To overcome such administration issues, extensive research has been focused on developing transdermal antipsychotic formulations. In this work, three microneedle (MN) systems were developed to deliver fluphenazine (FLU) systemically. A decanoic prodrug of FLU called fluphenazine decanoate (FLUD) was used in two of the MN formulations due to its high lipophilicity. FLU-D was loaded into dissolving MNs and nanoemulsion (NE)-loaded MNs. The parent drug FLU was loaded into poly(lactic-co-glycolic acid) (PLGA)-tipped MNs. All MN systems were characterised and evaluated in vitro and in vivo. The in vivo evaluation of the three developed MN systems showed their ability to deliver FLU into the systemic circulation, as the Cmax of FLU-D dissolving MNs was 36.11 ± 12.37 ng/ml. However, the Cmax of FLU-D NE loaded dissolving MNs was 12.92 ± 6.3 ng/ml and for FLU-PLGA tipped MNs was 21.57 ± 2.45 ng/ml. Compared to an intramuscular (IM) injection of FLU-D in sesame oil, the relative bioavailabilities were 26.96 %, 21.73 % and 42.45 % for FLU-D dissolving MNs, FLU-D NE dissolving MNs and FLU-PLGA tipped MNs, respectively. FLU plasma levels were maintained above the minimum human therapeutic limits for a week. Consequently, these various MN formulations are considered to be a viable options for the transdermal delivery of fluphenazine and its prodrug. The three MN systems developed offer patients a user-friendly, painless, and convenient long-acting delivery method for FLU. Reducing dosing frequency and using less invasive drug administration methods can enhance adherence and foster positive therapeutic outcomes. This study demonstrates the capability and adaptability of MNs technology to transport hydrophobic molecules from the skin to the systemic circulation.

Presumptive Fluphenazine-induced Hepatitis and Urticaria in a Horse

4-year-old Standardbred gelding (450 kg) was examined because of depression, poor appetite, and suspected liver disease. Eight days before examination, the horse had won a race. The next day, depression, muscle stiffness, and transient pyrexia (39.0uC) were observed. The horse was treated with single doses of flunixin meglumine a (1 mg/kg IV), phenylbutazone b (0.2 mg/kg PO), methocarbamol c (4.4 mg/kg PO), Nacetylcysteine d (6.6 mg/kg PO), and 5 L lactated Ringer’s solution IV. A CBC and serum biochemical profile performed 4 days before presentation revealed neutrophilia and moderate increases in serum concentration of the hepatic enzyme activities (Table 1). Moderate urticaria (hives) was present over the trunk of the horse. On examination, the horse was quiet but alert and was in good body condition. Initial physical examination revealed mild jaundice and mild clinical dehydration. The heart rate (36 bpm), respiratory rate (12 bpm), and rectal temperature (37.6uC) were within normal reference limits. Multiple raised, edematous, nonpruritic nodules (3–5 mm diameter), consistent with urticaria were observed over the trunk and the neck. Auscultation and percussion of the thorax and the abdomen was unremarkable. Neurologic examination was unremarkable. This was the only horse of 19 on the farm affected. Thirty-three days before referral, the horse had been empirically administered a single dose of a long-acting parenteral preparation of fluphenazine decanoate e (0.28 mg/kg IM) as a tranquilizer to control anxious behavior. The gelding had daily access to 2 species of weeds, which were estimated to occupy approximately 20% of the turnout paddock area. No grass was available in the paddock because of overgrazing. Nineteen other horses shared the same turnout paddock and had the same management. All horses had access over a fence to lush grass, which had been sprayed with a surfactant-free glyphosphate product f the week the subject horse was administered fluphenazine. Serum biochemical profiles conducted on the herdmates, 2 days before examination, revealed serum activity of hepatic enzymes and concentration of total bilirubin within reference limits. No other horses in the barn had been administered fluphenazine decanoate. Vaccines administered to the horse included equine influenza, rhinopneumonitis, tetanus toxoid, and West Nile virus. The last dose of which had been administered approximately 8 weeks before referral. Clinicopathologic abnormalities were limited to hyperbilirubinemia, increased serum activity of hepatic enzymes (glutamate dehydrogenase [GLDH], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], and alkaline phosphatase [AP]), and increased total bile acids concentration (Table 1). These findings were interpreted as indicative of impaired bile circulation and active hepatocellular damage. No changes compatible with an inflammatory process were identified. Plasma fibrinogen and blood ammonia concentrations were not determined at that time. Transabdominal ultrasound examination revealed normal hepatic architecture. A fecal bacterial culture for Salmonella spp. was negative. The initial therapy consisted of lactated Ringer’s solution (60 mL/kg/d IV), trimethoprim-sulfadioxine g (24 mg/kg IV q12h), and flunixin meglumine (1 mg/kg IV q24h). The diet was restricted to first-cut grass hay to avoid high dietary protein content. Taxonomic classification of the weed plant species reported by the owner revealed that the predominant plant was ‘‘redroot pigweed,’’ Amaranthus retroflexus (80% of weeds in paddock), and the other was ‘‘Lamb’s quarter,’’ Chenopodium album (20% of weeds in paddock). A. retroflexus has been associated with severe renal disease in cattle, 1 and C. album has been associated with nitrate toxicosis in cattle. 2 To the authors’

Fluphenazine plasma level monitoring for patients receiving fluphenazine decanoate

Background: Finding a dose of an antipsychotic for maintenance therapy that is both safe and effective can be difficult because clinicians are unable to titrate dose against clinical response in patients who are already stable. Therapeutic monitoring of antipsychotic plasma levels has the potential for helping clinicians in dosage selection. With this in mind, we evaluated the usefulness of monitoring fluphenazine plasma levels for patients with schizophrenia who were receiving maintenance treatment with fluphenazine decanoate. Method: Thirty-one patients with schizophrenia were randomly assigned to low, medium, or high (0.1–0.3, 0.3–0.6, 0.6–1.0 ng/ml) plasma levels of fluphenazine. The dose of fluphenazine decanoate was adjusted in order to maintain patients in their assigned range. Side effects, psychopathology, and psychotic exacerbations were measured during the year following randomization. Results: All of the psychotic exacerbations occurred during the first eight weeks following randomization, before patients had adequate time to reach their plasma level assignments. We did not find a relationship between plasma levels of fluphenazine and clinical outcomes or side effects. Conclusion: Our results do not provide support for the usefulness of monitoring fluphenazine plasma levels for patients receiving fluphenazine decanoate.

Tardive dyskinesia and serum iron indices

Background: This study was undertaken to evaluate whether peripheral (serum) markers of iron status are associated with severity of the choreoathetoid movements seen in tardive dyskinesia (TD). Methods: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male DSM-III diagnosed schizophrenic patients chronically treated with fluphenazine decanoate. The severity of choreoathetoid movements was assessed with the Abnormal Involuntary Movement Scale (AIMS), and akathisia was assessed with the Barnes scale. Results: A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. There were no significant associations between serum iron indices and akathisia ratings. Conclusions: The data suggest that choreoathetoid movements are associated with serum ferritin levels in chronically medicated male schizophrenic patients. This relationship does not seem to be caused by an association of these variable with age or plasma fluphenazine levels. In addition, the relationship seems to be specific, since other iron indices and another extrapyramidal side effect (akathisia) do not demonstrate a similar relationship. In view of reports that antipsychotic medications change normal iron metabolism and increase iron uptake into the brain, the current results could be interpreted to suggest that serum ferritin levels may be a risk factor for TD in patients treated with “classic” antipsychotic medications.

Sensitive method for the simultaneous measurement of fluphenazine decanoate and fluphenazine in plasma by high-performance liquid chromatography with coulometric detection.

A highly sensitive and specific high-performance liquid chromatographic method with coulometric detection was developed for the simultaneous assay of fluphenazine decanoate and fluphenazine in plasma. The extraction and sample clean-up procedures are simple, rapid to execute, yet yield chromatograms relatively free of any interference from endogenous plasma constituents, such that the extraordinary sensitivity of the coulometric detector can be exploited fully. This is the first analytical procedure for the simultaneous determination of fluphenazine decanoate and fluphenazine. The detection limits for both fluphenazine decanoate and fluphenazine were 0.1 ng/ml plasma and the limits of quantitation were 0.25 ng/ml plasma. Standard curves from 0.25 to 10 ng/ml were linear with coefficients of variation < 10%. The method was applied to measure plasma levels of fluphenazine decanoate and fluphenazine in patients under medication with 25-50 mg biweekly intramuscular (i.m.) injections of fluphenazine decanoate. It was possible to monitor the plasma levels of fluphenazine in all cases. Fluphenazine decanoate was present in measurable concentration in the plasma of 4 out of 5 patients who received biweekly i.m. injections of 50 mg fluphenazine decanoate. In a pilot experiment with a dog, the method was used to follow fluphenazine decanoate and fluphenazine plasma levels up to 13 days, at least, after i.m. single dose (10 mg/kg).

Monitoring plasma levels of fluphenazine during chronic therapy with fluphenazine decanoate

This study was conducted to examine the interpatient variability in steady-state plasma concentrations of fluphenazine by repeat depot intramuscular administration, and to determine the relationship between these concentrations and clinical state. Steady-state pre-dose concentrations of fluphenazine in plasma were measured using a sensitive and specific gas chromatography/mass spectrometry (GC/MS) assay in 24 patients with schizophrenia who were receiving continuous treatment with depot intramuscular fluphenazine decanoate. Clinical response was measured using the Andreasen Scale for positive and negative symptoms. Steady-state plasma concentrations of fluphenazine ranged from undetectable (< 0.1 ng/ml) to 27.9 ng/ml, with a median of 0.5 ng/ml. No significant associations were found between plasma concentration and dosage, or age and sex of the patient. Steady-state plasma concentrations in patients taking anticholinergic agents were significantly higher than in patients not receiving such drugs (P < 0.05 by Mann-Whitney U-test). Poorer control, expressed as the sum of the negative symptom scores or the sum of the positive and negative symptom scores, was related to higher log transformed plasma concentration of fluphenazine and higher fluphenazine decanoate dosage. The log transformed plasma concentrations of fluphenazine and the fluphenazine decanoate dosages were weakly related. Patients receiving another antipsychotic drug in addition to fluphenazine decanoate tended to have poorer clinical control and higher dosages of fluphenazine decanoate. These results indicate the useful role that plasma level monitoring can fulfil in identifying patients who are therapy-resistant despite high plasma levels.

Relation of plasma fluphenazine levels to treatment response and extrapyramidal side effects in first-episode schizophrenic patients

The aim of this study was to determine the relation between plasma fluphenazine levels and clinical response in first-episode schizophrenic patients. Data from 36 first-episode schizophrenic or schizoaffective inpatients diagnosed according to the Research Diagnostic Criteria were evaluated. The patients received open, standardized treatment with fluphenazine, 20 mg/day, for at least 4 weeks. Psychopathology was assessed biweekly, and plasma fluphenazine levels were ascertained weekly. Patients were classified as responders or nonresponders, and correlations between their neuroleptic levels and ratings of psychopathologic and extrapyramidal symptoms were computed. Plasma fluphenazine levels for weeks 1 through 4 were significantly correlated with each other but were not correlated with age, gender, diagnosis, or race. Mean neuroleptic levels (weeks 3 and 4) were not different between responders and nonresponders and were not correlated with measures of psychopathology or extrapyramidal symptoms. These results do not indicate an association between plasma fluphenazine levels and response to treatment or extrapyramidal side effects in first-episode schizophrenia. The disparity between the results of this study and those of previous studies may be due to methodological differences or to a biologically based difference between first-episode and chronic patients.

Clinical Perspectives of Some Neuroleptics Through Development and Application of Their Assays

Attempts to investigate relationships between plasma levels of neuroleptics and therapeutic outcome in schizophrenic patients have been hampered due to such factors as the chemical nature of these drugs, their metabolism, and the very heterogeneous nature of the disease states. Two clinical studies are described that investigate the relationship between plasma levels of fluphenazine (FLU) and its metabolites and therapeutic outcome in schizophrenic patients. In the first of these studies the levels of FLU and fluphenazine sulfoxide (FLUSO) in schizophrenics receiving either 5 or 25 mg of fluphenazine decanoate (FLUD) intramuscularly every 2 weeks were monitored. Patients given 25 mg of FLUD required 3 months to reach plasma level steady state. The results suggest that such patients, when being switched from the oral to the depot formulation of FLU, should continue to receive oral supplementation during the 1st 3 months after conversion. The relationship between log-transformed plasma levels at 26 and 38 weeks with subsequent psychotic exacerbation was investigated with the use of logistic regression and survival analysis. Both demonstrated significant relationships between FLU plasma levels and a risk of psychotic exacerbation at 26 and 38 weeks. The possibility of any correlations between neurological side effects and plasma concentrations were also investigated, with statistically significant correlations between FLU levels and akinesia found at 2 and 26 weeks. In the second of these studies the levels of FLU, FLUSO, 7-hydroxyfluphenazine (7-OHFLU), and fluphenazine N4'(-)-oxide (FLUNO) in schizophrenics receiving 5, 10, or 20 mg of oral fluphenazine dihydrochloride daily for 4 weeks were monitored. The relationships between log-transformed plasma levels, disabling side effects, and global improvement were examined by logistic regression for the 4-week period. The study showed a significant correlation between increases in both plasma levels and disabling side effects such that at a plasma level of 2.7 ng/ml, approximately 90% of acutely ill patients experienced disabling side effects. Conversely, the study also showed that at a plasma level of 0.67 ng/ml, 48% of patients experienced improvement without the development of disabling side effects. When relationships between metabolite levels, disabling side effects, and global improvement were examined by logistic regression, a stronger correlation between disabling side effects and FLUNO levels than between side effects and FLU levels was found.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of extended depot fluphenazine treatment and withdrawal on social and other behaviors ofCebus apella monkeys

To examine whether or not prolonged exposure to a depot neuroleptic has either residual or "tardive pathological" effects on normal behavior, 38 Cebus apella monkeys were observed daily for 108 weeks. The issue of stress influencing such effects was also addressed. During weeks 25-48 half of the monkeys received 0.22 mg/kg fluphenazine decanoate, IM, every 3 weeks, with the dose increased to 0.33 mg/kg during weeks 49-72. Behavioral measures were combined to form composite behavioral variables which quantify four major aspects of behavior: self- and environment-directed behavior, affiliation, aggression, and normal locomotor activity. Mean plasma fluphenazine levels at 48 h post-injection were 0.13 (+/- 0.03) ng/ml for injections 3-8 and 0.24 (+/- 0.07) ng/ml for injections 11-16. The pre-study null hypothesis that the four major aspects of behavior would not be adversely affected by this treatment during the drug-discontinuation phase of the study (weeks 73-108) was not statistically negated. There were highly significant decreases in self- and environment-directed behaviors and affiliation during the treatment periods, implying that treatment may contribute to the negative symptoms of treated schizophrenics. Stress reduced the above effects. Aggression showed some increase during early drug discontinuation, accentuated by stress. Recovery of normal (baseline) behavioral scores began by week 7 after the last treatment. Mild (bucco-lingual) tardive dyskinesias persisted in 30% of the animals for a prolonged time.

Plasma Levels of Fluphenazine in Patients Receiving Fluphenazine Decanoate Relationship to Clinical Response

The levels of fluphenazine and fluphenazine sulphoxide in schizophrenic patients who were randomly assigned to receive either 5 mg or 25 mg of fluphenazine decanoate every two weeks were monitored. Patients treated with 25 mg of fluphenazine decanoate required three months to reach a steady-state plasma level, indicating that those patients who are being converted from oral to depot fluphenazine should continue to receive oral supplementation during the first three months of treatment with fluphenazine decanoate. Plasma levels of fluphenazine sulphoxide were lower than levels of fluphenazine. At six and nine months following randomisation, there was a statistically significant relationship between lower fluphenazine plasma levels and an increased risk of psychotic exacerbations. A relatively weak relationship was found between fluphenazine plasma levels and akinesia, but non-significant relationships between fluphenazine levels and other neurological side-effects including akathisia, retardation, and tardive dyskinesia. Monitoring the plasma levels may be helpful to clinicians who are attempting to treat stabilised patients with the lowest effective dose of fluphenazine decanoate.

Plasma fluphenazine levels and clinical response in newly admitted schizophrenic patients

Plasma fluphenazine levels and clinical response in newly admitted schizophrenic patients

Plasma levels of Fluphenazine and prolactin in maintenance treatment of schizophrenia

Plasma levels of Fluphenazine and prolactin in maintenance treatment of schizophrenia

Plasma levels of fluphenazine and prolactin in psychiatric patients.

A total of 100 patients receiving fluphenazine (FPZ) decanoate for at least 12 months (96 schizophrenics and 4 other diagnoses) were investigated for plasma levels of FPZ and prolactin on the day of injection (day 0) and 7 days later (day 7). The plasma FPZ level significantly correlated with the weekly dose of FPZ. The plasma FPZ level per weekly FPZ dose multiplied by 100 (the FPZ ratio) showed a 20-fold variation. The FPZ ratio was significantly higher in the day- and in-patients (hospital-patients) than in out-patients. The plasma prolactin level significantly correlated with the plasma FPZ level but the prolactin to FPZ ratio negatively correlated with the plasma FPZ level. The prolactin to FPZ ratio was lower in the hospital patients than in the out-patients. This may suggest either that the high prolactin to FPZ ratio is an indicator of the therapeutic efficacy of FPZ or that there are at least two biologically distinct subgroups, one with a sharp prolactin response to FPZ, therefore with good prognosis, and another with the reverse direction.

A Highly Sensitive and Specific Radioimmunoassay for Quantitation of Plasma Fluphenazine

Antisera of high sensitivity and selectivity were obtained from rabbits immunized with conjugates of hemisuccinylated fluphenazine and porcine thyroglobulin. The antiserum selected (titer 1:6000) for the development of the RIA was obtained after a priming dose and a single iv booster injection three months later. This antiserum had negligible crossreactivity with known available metabolites of fluphenazine (FPZ) and an affinity constant of 2 × 1010 L/mol. Tritiated FPZ was further purified by HPLC and used as a ligand. The method detects as little as 20 pg/mL of plasma (4 pg/RIA tube) after 1 mL of plasma is extracted. The extraction was performed at a basic pH with heptane: isoamyl alcohol (99:1); the solvent was then back extracted using an acetic phosphate buffer. Recoveries were uniformly high (88.6 ± 2.1%), and this aqueous buffer extract was used directly in the RIA procedure. The assay has intra- and interassay coefficients of variation of 5.8 and 8.2%, respectively, in a plasma concentration of 95 pg/mL. Results using this procedure have been cross validated against an HPLC procedure (r = 0.952, slope = 1.032, intercept = 0.009, n = 18). In a single-dose FPZ study (10 mg, po), plasma FPZ levels in 25 normal volunteers could be monitored>48 h post dose. Single plasma level profiles, after an initial injection of 12.5 mg of FPZ decanoate, could be measured>36 d, and, in some cases, up to 100 d post dose.

Pharmacokinetic and pharmacodynamic studies on high doses of fluphenazine.

Six chronic schizophrenics--earlier refractory to recommended doses of neuroleptic drugs but eventually responding to 250 mg fluphenazine heptanoate weekly--participated in a pharmacokinetic study. Five out of the six patients showed rather constant steady state plasma fluphenazine values on a 250 mg depot weekly. After depot drug withdrawal, the single oral dose pharmacokinetics on 400 mg fluphenazine showed the same variations in Cmax, tmax, t 1/2 and AUC as are observed when recommended doses of fluphenazine are used. We thus could not demonstrate any dose-dependent pharmacokinetics on high oral fluphenazine doses. In half the patients, a biphasic decay in the plasma concentration curve indicated at least two compartments. The patients were then studied for up to 2 years on 200-500 mg fluphenazine as a single daily dose. The fluphenazine plasma levels were rather constant in the individual patients during this period. The plasma prolactin values were related to the fluphenazine values even in the high value area, thus showing a persistent pharmacodynamic variation capacity. The clinical part of the study did not show any relevant findings.

Persistence of Fluphenazine in Plasma after Decanoate Withdrawal

We discontinued fluphenazine decanoate using a double-blind, crossover random order design, in 12 recent onset clinically stable schizophrenics who had been given fluphenazine decanoate 12.5 mg intramuscularly every 2 weeks for at least 1 year prior to drug withdrawal. Each condition (drug or placebo) lasted 12 weeks. Using a radioimmunoassay verified by comparison to a gas chromatographic-mass spectrometric method, plasma fluphenazine levels were measured every 2 weeks during drug continuation and drug withdrawal conditions. No patient relapsed over the 24-week period of the study. Mean fluphenazine levels between drug continuation and withdrawal conditions showed a progressively larger difference over time, although significant differences were not seen until week 8. By week 12 after drug withdrawal, 33% of subjects still showed notable plasma fluphenazine levels. On the basis of our preliminary findings, we suggest that 2-week intervals between injections may be too short and that wider intervals may achieve similar clinical results.

Fluphenazine decanoate dose and severity of depression in patients with post-psychotic depression

The authors examined the fluphenazine decanoate dose and the fluphenazine plasma levels in comparison with measures of severity of depression in schizophrenic and schizoaffective patients. All patients were selected for study on the basis of having stable, syndromally defined, antiparkinsonian non-responsive syndromes of post-psychotic depression. No meaningful relationships were found. The implications of this observation with regard to the notion that depressive symptomatology in such patients is neuroleptic-induced is discussed.

The sulfoxidation of fluphenazine in schizophrenic patients maintained on fluphenazine decanoate.

Highly sensitive radioimmunoassays were applied to study the sulfoxidation of fluphenazine in 30 schizophrenic patients maintained on either 5 mg or 25 mg fluphenazine decanoate by intramuscular injection every 14 days over a period of 6 months. The presence of the sulfoxide metabolite was detected in all but one of the patients, such that 97% of the 340 plasma samples analysed contained the metabolite. Interpatient variations in plasma levels of fluphenazine, fluphenazine sulfoxide, and in drug to metabolite plasma level ratios were several fold higher than the corresponding intrapatient variations at both dosages. There were statistically significant tendencies for mean plasma fluphenazine levels to rise and mean plasma sulfoxide levels to fall over the 6-month period of study among patients on the high dose, consistent with our previously reported observation that it takes 3-6 months to establish a steady state of fluphenazine with this dosage regimen. By contrast, there were no statistically significant changes in mean plasma levels of either fluphenazine or its sulfoxide in patients on the low dose. Nevertheless, there was a significant rise in fluphenazine to fluphenazine sulfoxide mean plasma level ratios in both dosage groups. It is difficult to assess the significance of the changes in the drug to metabolite ratios with time, since there are no kinetic data on the phase II metabolism (conjugation) of fluphenazine or fluphenazine sulfoxide. This study shows that sulfoxidation is an important major pathway in the metabolism of intramuscularly-administered fluphenazine, and implies that metabolic sites other than gut wall are also involved in the process.

Fluphenazine activity and antipsychotic response.

Plasma fluphenazine levels and plasma total neuroleptic activity (as quantitated by the neuroleptic receptor binding assay) were related to therapeutic response in 15 DSM-III schizophrenic patients who received a predetermined, fixed dose of fluphenazine for 14 days. Mean neuroleptic activity of the plasma was 84% greater than can be accounted for by the parent fluphenazine alone, and varied widely between patients. A sigmoidal relationship between total neuroleptic activity of plasma and response was found, with a continued plateau of response at higher total neuroleptic levels. Furthermore, the RBA data suggested (P less than 0.002) that two populations of drug-responsive schizophrenics exist which may be discriminated by the total D2 binding activity of plasma required for response.

Plasma levels of fluphenazine during fluphenazine decanoate treatment in schizophrenia.

The authors measured plasma fluphenazine levels in 20 schizophrenic patients receiving 25 or 50 mg fluphenazine decanoate (FPZ-D) by IM injection every 2 weeks. The plasma levels were determined by a sensitive gas-liquid chromatographic (GLC) assay with a nitrogen detector device developed in their laboratory. Using this chemical assay method, they replicated the finding of a sharp initial plasma peak within 24 h after the injection followed by a low but rather stable plasma level as previously reported by nonchemical assay methods. The interval plasma levels (averages of day 4-10 after injection) ranged from 0.17-0.61 ng/ml in 10 patients who received 25 mg; and 0.20-0.93 ng/ml in 7 patients who received 50 mg FPZ-D every 2 weeks. This four-fold variation in plasma levels during FPZ-D injection was smaller than previously reported levels achieved with oral antipsychotic drug treatment. Based on the study of plasma levels achieved with FPZ-D injection and oral FPZ-H (fluphenazine HC1) in 6 patients, the dosage requirement of FPZ-D appeared to be difficult to predict from the oral dosage of FPZ-H in the same patient. Two weeks past injection, fluphenazine was undetectable in approximately half the samples with the GLC method. Thus, radioimmunoassay or radioreceptor assay, which also measures metabolites, might be more suitable for the study of plasma levels in patients receiving FPZ-D injection.