Does changing from a first generation antipsychotic (perphenazin) to a second generation antipsychotic (risperidone) alter brain activation and motor activity? A case report.

BACKGROUND: In patients with schizophrenia, altered brain activation and motor activity levels are central features, reflecting cognitive impairments and negative symptoms, respectively. Newer studies using nonlinear methods have addressed the severe disturbances in neurocognitive functioning that is regarded as one of the core features of schizophrenia. Our aim was to compare brain activation and motor activity in a patient during pharmacological treatment that was switched from a first- to a second-generation antipsychotic drug. We hypothesised that this change of medication would increase level of responding in both measures. CASE PRESENTATION: We present the case of a 53-year-old male with onset of severe mental illness in adolescence, ICD-10 diagnosed as schizophrenia of paranoid type, chronic form. We compared brain activation and motor activity in this patient during pharmacological treatment with a first-generation (perphenazin), and later switched to a second-generation (risperidone) antipsychotic drug. We used functional magnetic resonance imaging (fMRI) to measure brain activation and wrist worn actigraphy to measure motor activity. CONCLUSION: Our study showed that brain activation decreased in areas critical for cognitive functioning in this patient, when changing from a first to a second generation antipsychotic drug. However the mean motor activity level was unchanged, although risperidone reduced variability, particularly short-term variability from minute to minute. Compared to the results from previous studies, the present findings indicate that changing to a second-generation antipsychotic alters variability measures towards that seen in a control group, but with reduced brain activation, which was an unexpected finding.

Effect of perphenazine enanthate in Pyrenean chamois (Rupicapra pyrenaica).

Perphenazine enanthate was used to allow adaptation to captivity in 11 Pyrenean chamois (Rupicapra pyrenaica). At the time of capture, all animals received 0.10 mg/kg of acepromazine maleate and 2.5 mg/kg of perphenazine enanthate intramuscularly. The effect was evaluated by means of three behaviors: alertness, defecation, and flight distance. The tranquilization and lack of fear of humans of all animals were determined and the usefulness of this long-acting tranquilizer for chamois adaptation to captivity was confirmed.

Bl-1020, a new γ-aminobutyric acid-enhanced antipsychotic: results of 6-week, randomized, double-blind, controlled, efficacy and safety study.

OBJECTIVE: BL-1020 is a γ-aminobutyric acid (GABA)-enhanced antipsychotic that combines dopamine antagonism with GABA agonist activity. On the basis of animal models, we tested the hypotheses that BL-1020 would be effective in ameliorating both psychotic symptoms and cognitive impairments, with a favorable safety profile in acutely ill schizophrenia patients. METHOD: 363 hospital-based psychiatric patients in India, Romania, and United States aged 18 to 65 years and meeting criteria for DSM-IV-TR diagnosis of chronic schizophrenia were randomized double-blind to receive BL-1020 10 mg/d, BL-1020 20-30 mg/d, placebo, or risperidone (2-8 mg/d) for 6 weeks. The main outcome measures were the positive and negative syndrome scale (PANSS), brief assessment of cognition in schizophrenia, readiness for discharge questionnaire, clinical global impressions scale (CGI) , and extrapyramidal symptom rating scale. The study ran from July 2008 to June 2009. RESULTS: BL-1020 20-30 mg was significantly better than placebo on PANSS (P = .02) and CGI (P < .001) measurements, with no significant differences noted between BL-1020 20-30 mg and risperidone. There were no significant differences in the maximum change on extrapyramidal symptom rating scale between risperidone and BL-1020 20-30 mg, and both were significantly worse (P < .001) than placebo. BL-1020 20-30 mg was associated with significantly greater improvements on cognitive functioning as measured by the brief assessment of cognition in schizophrenia composite score when compared to placebo (effect size = 0.50, P = .009), risperidone (effect size = 0.43, P = .019), and BL-1020 10 mg (effect size = 0.42, P = .013) after 6 weeks. CONCLUSIONS: BL-1020 appears to be an effective antipsychotic with possible procognitive effects that will need to be further tested for short- and long-term effects. A further randomized controlled trial using the U.S. Food and Drug Administration-recommended Measurement and Treatment Research to Improve Cognition in Schizophrenia cognitive battery is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00567710.

An open-label tolerability study of BL-1020 antipsychotic: a novel gamma aminobutyric acid ester of perphenazine.

BACKGROUND: BL-1020, a novel gamma aminobutyric acid (GABA) ester of perphenazine, is a new oral antipsychotic with a strong affinity for dopamine and serotonin receptors. Unlike first- and second-generation antipsychotics, it has agonist activity at GABA(A). OBJECTIVE: This is the first study to examine tolerability and safety of BL-1020 in schizophrenia. METHODS: This was a phase-II, open-label, multicenter, 6-week study treating patients (n = 36) with chronic schizophrenia. Dosing started at 20 mg/d and increased over 7 days to 40 mg/d. Weekly assessments were conducted. RESULTS: All but 1 patient was titrated to 30 mg/d at day 4; on day 7, 30 were titrated to 40 mg/d. Four patients discontinued the study prematurely. There was no clinically relevant increase in vital signs, sedation, dizziness, or other central nervous system effects or electrocardiogram or laboratory abnormalities and a small increase in weight. Ten patients experienced extrapyramidal symptoms (EPS) requiring treatment with an anticholinergic; 4 patients were unable to reach maximum dose because of EPS. Extrapyramidal Symptom Rating Scale did not indicate clinically significant changes in EPS. The most common adverse event was insomnia (6 patients); other frequent adverse effects (all n = 3) were extrapyramidal disorder, headache, parkinsonism, tremor, and hyperprolactinemia. There was improvement on Positive and Negative Syndrome Scale and Clinical Global Impression of Change with 22 patients showing at least 20% decrease by end point on Positive and Negative Syndrome Scale and 31 patients showing at least minimal improvement on Clinical Global Impression of Change. CONCLUSIONS: These data suggest that 20 to 40 mg/d of BL-1020 is associated with clinically relevant improvement of psychosis with no worsening of EPS and support further testing in randomized controlled trials.

Thermally induced intramolecular oxygen migration of N-oxides in atmospheric pressure chemical ionization mass spectrometry.

N-Oxides are known to undergo three main thermal degradation reactions, namely deoxygenation, Cope elimination (for N-oxides containing a ß-hydrogen) and Meisenheimer rearrangement, in atmospheric pressure chemical ionization mass spectrometry (APCI-MS). The ions corresponding to these thermal degradants observed in the ensuing APCI mass spectra have been used to identify N-oxides as well as to determine the N-oxidation site when the analyte contains multiple tertiary amine groups. In this paper, we report a thermally induced oxygen migration from one N-oxide amine to another tert-amine group present in the same molecule through a six-membered ring transition state during APCI-MS analysis. The observed intramolecular oxygen migration resulted in the formation of a new isomeric N-oxide, rendering the results of the APCI-MS analysis more difficult to interpret and potentially misleading. In addition, we observed novel degradation behavior that happened after the Meisenheimer rearrangement of the newly formed N-oxide: a homolytic cleavage of the N-O bond instead of elimination of an aldehyde or a ketone that usually follows the rearrangement. Understanding of these unusual degradation pathways, which have not been reported previously, should facilitate structural elucidation of N-oxides using APCI-MS analysis.

BL-1020, an oral antipsychotic agent that reduces dopamine activity and enhances GABAA activity, for the treatment of schizophrenia.

In schizophrenia, a psychiatric disorder that affects approximately 1% of the global population and is associated with substantial disability, a significant proportion of patients (usually estimated to be at least 30%) fail to respond to treatment, and many patients have difficulty continuing treatment because of side effects. At the time of publication, all available medications for schizophrenia targeted dopamine and other monoamine neurotransmitters. However, a substantial amount of research suggests that patients with schizophrenia have underlying deficits within the GABA neurotransmitter system. BL-1020, being developed by BioLineRx Ltd under license from Tel Aviv University Ltd and Bar-Ilan Research & Development Co Ltd, is a novel compound consisting of the well-established antipsychotic drug perphenazine and GABA. Preclinical studies of BL-1020 indicated that the compound penetrated the brain and was efficacious in rodents, with a significant reduction in side effects compared with the administration of perphenazine. BL-1020 was well tolerated in all clinical trials conducted, and clinically meaningful improvements were demonstrated in phase II trials in patients with schizophrenia. Further data from phase II and subsequent phase III trials will be required to derive conclusions for BL-1020 regarding overall efficacy.

Effect of perphenazine enanthate on open-field test behaviour and stress-induced hyperthermia in domestic sheep.

The open-field test (OFT) and stress-induced hyperthermia (SIH) have been used to measure individual differences in fear. The present study has been designed as a pharmacological validation of OFT and SIH as indicators of fear in sheep using perphenazine enanthate (PPZ), a long-acting neuroleptic. Twenty four ewes of two breeds, Lacaune and Ripollesa, were tested in an arena measuring 5mx2.5m. Treatment group received one dose of 1.5mg/kg of PPZ and control group received sterile sesame oil. All animals were tested for 10min and behaviours were recorded. Rectal temperature was measured at the beginning (T1) and at the end (T2) of the test. SIH was defined as the difference between T2 and T1. Sheep were tested on days 1, 2, 3, 4, 7 and 9 after PPZ injection. Variables were analysed using a mixed model. PPZ decreased bleats on days 2, 3, 4 and the SIH response on days 2 and 3. Breed differences were observed. Treated animals showed positive correlations between SIH and bleats; squares entered; attempts to escape and negative correlation between SIH and visits to the food bucket. Our results suggest that behaviour and SIH on the OFT are useful measures of fear in sheep.

BL-1020, a novel antipsychotic candidate with GABA-enhancing effects: D2 receptor occupancy study in humans.

BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to gamma-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D(2)) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [(11)C]raclopride, assessed the extent and duration of D(2) receptor occupancy (D(2) RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D(2) RO. The 32 mg dose of BL-1020 resulted in an average D(2) RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D(2) RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D(2) ROs ranging from 52 to 66% at a steady state.

BL-1020: a novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia.

UNLABELLED: Reduced brain gamma-amino-butyric acid (GABA) participates in the pathogenesis of schizophrenia. GABA scarcely penetrates the brain. We evaluated the pharmacological properties of BL-1020, a novel GABA ester of perphenazine. Oral BL-1020 or perphenazine were assessed in acute and subchronic schizophrenia rat models. Catalepsy, serum prolactin, receptor binding profile and cortical (PFC), hippocampal (Hip) and dopamine (DA) levels were determined. Radioactive [14C] labeled BL-1020 was used for pharmacokinetics (PK). Acute and subchronic treatment with BL-1020 antagonized amphetamine-induced hyperactivity, with significantly lower catalepsy and sedation compared to equimolar perphenazine. At the same time, BL-1020 increased DA release in the PFC and Hip. BL-1020 and perphenazine stimulated prolactin secretion equally. BL-1020 displayed strong DA and serotonin (5HT) receptor inhibition (D(2L)K(iz)=0.066 nM, D(2S)K(i)=0.062 nM, 5-HT(2A)K(i)=0.21 nM). PK data revealed that BL-1020 penetrated the brain. CONCLUSIONS: The advantages of BL-1020 for treatment of schizophrenia stem from its being a DA/5HT antagonist and a GABAergic agonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation.

A mutual prodrug ester of GABA and perphenazine exhibits antischizophrenic efficacy with diminished extrapyramidal effects.

The perphenazine and fluphenazine GABA esters 3 and 4 evaluated in rat models for antipsychotic activity displayed a significant decrease of catalepsy associated with increased prolactin blood levels. Efficacy was evaluated in the d-amphetamine-induced hyperactivity model, where perphenazine abolished hyperactivity and induced sedation and catalepsy, whereas 3 reduced hyperactivity without sedation or catalepsy. Thus, 3 (BL-1020) constitutes a prototype of novel antipsychotics possessing GABAergic activity. A phase II study is in progress.

Depot perphenazine decanoate and enanthate for schizophrenia.

BACKGROUND: Antipsychotic drugs are usually given orally but compliance with medication given by this route may be difficult to quantify. The development of depot injections in the 1960s gave rise to extensive use of depots as a means of long-term maintenance treatment. Perphenazine decanoate and enanthate are depot antipsychotics that belong to the phenothiazine family and have a piperazine ethanol side chain. OBJECTIVES: To assess the effects of depot perphenazine decanoate and enanthate versus placebo, oral antipsychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Group Register (June 1998), Biological Abstracts (1982-1998), the Cochrane Library (Issue 2, 1998), EMBASE (1980-1998), MEDLINE (1966-1998), and PsycLIT (1974-1998) by searching the Cochrane Schizophrenia Group Register (March 2004). References of all identified trials were also inspected for more studies and industry contacted. SELECTION CRITERIA: We compared randomised clinical trials focusing on people with schizophrenia where depot perphenazine decanoate and enanthate, oral antipsychotics or other depot preparations. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality rated them and extracted data. For dichotomous data we estimated the Relative Risk (RR) with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat statistic (NNT). Analysis was by intention-to-treat. MAIN RESULTS: Only four studies (Ahlfors 1980, Eufe 1979, Knudsen 1985c, Tegeler 1979), randomising a total 313 people could be included in this review and this combined with an overall lack of usable data limits any interpretation of results. Perphenazine enanthate was not significantly any better or worse than other depot antipsychotics in most of the main outcomes such as global state, relapse or leaving the study early. We found some differences favouring the control groups for adverse effects. One study (Ahlfors 1980) of six months' duration (n=172), compared perphenazine enanthate to clopenthixol decanoate. There were no differences between the two groups for outcomes of global improvement, relapse and leaving the study early. More people in the perphenazine enanthate group, however, required anticholinergic drugs than those allocated to clopenthixol decanoate (RR 1.12 CI 1.0 to 1.2, NNT 10).A single study (n=64, duration six weeks) compared perphenazine enanthate and its longer acting decanoate ester. Data on relapse and leaving the study early failed to show convincing differences. The enanthate group, however, experienced more movement disorders (RR 1.36, CI 1.1 to 1.8 NNT 5) than those allocated the decanoate ester of the same drug and required more anticholinergic drugs (RR 1.47 CI 1.1 to 2.0, NNT 4). AUTHORS' CONCLUSIONS: Depot perphenazine is in clinical use in the Nordic countries, Belgium, Portugal and the Netherlands. At a conservative estimate, a quarter of a million people suffer from schizophrenia in those countries and could be treated with depot perphenazine. The total number of participants in the four trials with useful data is 313. None of the studies observed the effects of oral versus depot antipsychotic drugs. Until well conducted and reported randomised trials are undertaken clinicians will be in doubt as to the effects of perphenazine depots and people with schizophrenia should exercise their own judgement or ask to be randomised.

Comparison of the effect of the R2 phenothiazine ring substituent on fluphenazine and perphenazine interactions with cyclodextrins.

The effect of -CF3 R2 fluphenazine (FLF) and -Cl R2 perphenazine (PF) substituents on interactions of these phenothiazine derivatives with cyclodextrins (CD) was compared. Inclusion complexes of protonated and basic forms of FLF and PF with CDs were obtained in HCl 0.01 mol/L (pH 1.9 or 2.1), in phosphate buffer (pH 5.8) and in Britton-Robinson's buffer (pH 10.2) solutions and studied using spectral method. It was established. that the uncharged forms of both phenothiazine derivatives interact with CDs stronger than protonated molecules and that the perphenazine-CD inclusion complexes characterize greater apparent stability constants in comparison to adequate fluphenazine complexes. The thermodynamic parameters, estimated from linear Van't Hoff plot, suggest that the van der Waals forces accompanied by hydrophobic effects were operating in the investigated FLF-CD and PF-CD systems. The effect of pH and presence of CD on photostability of FLF or PF was also compared. The photochemical decomposition of both phenothiazine derivatives, in the absence and in the presence of CDs, proceeds according to the first order reaction. It was also established that independent on the charge of molecule, perphenazine was more stabile than fluphenazine and that the inclusion complexation with CDs improved the photostability of both drugs. The data of 2D NMR analysis suggest, that the aromatic portion of FLF and PF molecules, without R2 substituent, tend to the interior of CD.

Noninvasive monitoring of adrenocortical activity in roe deer (Capreolus capreolus) by measurement of fecal cortisol metabolites.

A method for measuring glucocorticoids noninvasively in feces of roe deer was established and validated. The enzyme immunoassay (EIA) measures 11,17-dioxoandrostanes (11,17-DOA), a group of cortisol metabolites. Such measurement avoids blood sampling and reflects a dampened pattern of diurnal glucocorticoid secretion, providing an integrated measure of adrenocortical activity. After high-performance liquid chromatography, the presence of at least three different immunoreactive 11,17-DOA in the feces of roe deer was demonstrated. The physiological relevance of these fecal cortisol metabolites to adrenocortical activity was evaluated with an adrenocorticotropic hormone challenge test: cortisol metabolite concentrations exceeded pretreatment levels (31-78 ng/g) up to 13-fold (183-944 ng/g) within 8-23 h. Starting from basal levels between 13 and 71 ng/g, a suppression of adrenocortical activity after dexamethasone administration, indicated by metabolite levels close to the detection limit, was obtained 36-81 h after treatment, whereas unmetabolized dexamethasone was detectable in feces 12 h after its injection. Fecal glucocorticoid metabolite assessment via EIA is therefore of use in the monitoring of adrenocortical activity in roe deer. In a second experiment, capture, veterinary treatment, and transportation of animals were used as experimental stresses. This resulted in a 7.5-fold increase of fecal metabolites (1200 +/- 880 ng/g, mean +/- SD) compared to baseline concentrations. The administration of a long-acting tranquilizer (LAT), designed to minimize the physiological stress response, 2 days prior to a similar stress event led to a reduced stress response, resulting in only a 4-fold increase of fecal metabolites (650 +/- 280 ng/g; mean +/- SD). Therefore, LATs should be further investigated for their effectiveness in reducing stress responses in zoo and wild animals, e.g., when translocations are necessary.

Evaluation of long-term sedation in cheetah (Acinonyx jubatus) with perphenazine enanthate and zuclopenthixol acetate.

Two long-acting neuroleptics were used to tranquilize nine captive cheetahs (Acinonyx jubatus). Perphenazine enanthate (3.0 mg/kg) and zuclopenthixol acetate (0.6 mg/kg) were each administered to separate groups of three cheetahs in a double blind trial. Both products were administered together to a third group of three animals at the same dosages. Behavioral effect, duration of effect, and possible side effects were observed by a predefined protocol. Under standardized holding conditions, the cheetahs were observed 5 days before drug administration and 14 days after administration. Daily activity was defined and statistically evaluated by a U-test. A significant reduction of activity was observed after administration in all three trials. Zuclopenthixol acetate at 0.6 mg/kg alone and in combination with perphenazine enanthate caused inappetence, ataxia, extra pyramidal reactions, akathisia, and prolapse of the third eyelid. Zuclopenthixol acetate should not be used in cheetahs. Perphenazine enanthate did not cause inappetence, reduced appetite, or any of the previously mentioned side effects when used alone. It produced satisfactory tranquilization and is suitable and safe for cheetahs at 3.0 mg/kg. This dosage should be varied depending on health, age, and temperament of the individual cheetah.

Depot perphenazine decanoate and enanthate for schizophrenia.

BACKGROUND: Anti-psychotic drugs are usually given orally but compliance with medication given by this route may be difficult to quantify. The development of depot injections in the 1960s gave rise to extensive use of depots as a means of long-term maintenance treatment. Perphenazine decanoate and enanthate are depot antipsychotics that belong to the phenothiazine family and have a piperazine ethanol side chain. OBJECTIVES: To assess the effects of depot perphenazine decanoate and enanthate versus placebo, oral anti-psychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. SEARCH STRATEGY: Biological Abstracts (1982-1998), the Cochrane Library (Issue 2, 1998), the Cochrane Schizophrenia Group's Register (June 1998), EMBASE (1980-1998), MEDLINE (1966-1998), and PsycLIT (1974-1998) were searched. References of all identified trials were also inspected for more studies and industry contacted. SELECTION CRITERIA: Randomised clinical trials focusing on people with schizophrenia where depot perphenazine decanoate and enanthate, oral anti-psychotics or other depot preparations were compared. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality rated and data extracted. For dichotomous data Peto odds ratios (OR) with the 95% confidence intervals (CI) were estimated. Where possible, the number needed to treat statistic (NNT) was calculated. Analysis was by intention-to-treat. MAIN RESULTS: One study of six months duration, compared perphenazine enanthate to clopenthixol decanoate. There was no differences between the two for outcomes of global improvement, relapse and leaving the study early. More people in the perphenazine enanthate group required anticholinergic drugs than those allocated to clopenthixol decanoate (OR 3.6 CI 1.2-10, NNT 10). A single study (n=64, duration six weeks) compared perphenazine enanthate and its longer acting decanoate ester. Data on relapse and leaving the study early failed to show convincing differences. The enanthate group, however, experienced more movement disorders (OR 0.2 CI 0.06-0.7) than those allocated the decanoate ester of the same drug (NNT 4.0) and required more anticholinergic drugs (OR 0.2 CI 0.08-0.7, NNT 3.7). REVIEWER'S CONCLUSIONS: Depot perphenazine is in clinical use in the Nordic countries, Belgium, Portugal and the Netherlands. At a conservative estimate a quarter of a million people suffer from schizophrenia in those countries and could be treated with depot perphenazine. The total number of participants in the two trials with useful data is 236. Neither study observes the effect of oral versus depot antipsychotic drugs. Until well conducted and reported randomised trials are undertaken clinicians will be in doubt as to the effects of perphenazine depots and people with schizophrenia should exercise their own judgement or ask to be randomised.

Dopamine D2-receptor density in humans as assessed with SPET and the new high-affinity ligand 123I-NCQ298: a pilot study.

Astra (S)-3-[123I]iodo-5,6-dimethoxyl-N-[(1-ethyl-2-pyrrolidinyl)methyl] -salicylamide (123I-NCQ298) is a new high-affinity D2-receptor ligand for use in single photon emission tomography (SPET) studies. We have studied the biodistribution and absorbed radiation dose of 123I-NCQ298 in humans. The mean effective dose for adults was 0.055 mSv MBq(-1). Brain uptake and clearance was measured with a head dedicated SPET camera. 123I-NCQ298 showed specific uptake in the basal ganglia with a low clearance rate (time constant of 9-34 h). The extrastriatal binding was variable (average 30%, maximum 60% of that in the basal ganglia at 1 h), but with a clearance rate twice that of the basal ganglia. The fairly high level of extrastriatal binding precluded the use of a quotient between the basal ganglia and cerebellum-to-frontal cortex 123I-NCQ298 concentration as a measure for basal ganglia D2-receptor density. Chronic schizophrenic patients treated with conventional neuroleptics had a decreased affinity for 123I-NCQ298 in the basal ganglia in the range 10-60% of the median value for the control, untreated subjects.

Large variations of plasma levels during maintenance treatment with depot neuroleptics.

BACKGROUND: Stability of neuroleptic medication has been associated with optimal clinical effect and minimal side-effects. Depot administration is assumed to yield better stability. METHOD: Thirty patients on depot neuroleptic treatment were followed during three years with repeated measurements of plasma level and concurrent ratings of clinical symptoms and side-effects. RESULTS: Of 120 blood samples 35 (29%) measurements were outside +/-2 s.d. measurement error (expected 5%). Perphenazine levels were more variable (46%) than haloperidol (25%) and flupenthixol (12.5%). No relationship was found between side-effect ratings and fluctuations of plasma levels. CONCLUSION: Depot neuroleptic medication does not eliminate a clinically unwanted and sometimes marked variation in plasma level.

Subjective experience of treatment, side-effects, mental state and quality of life in chronic schizophrenic out-patients treated with depot neuroleptics.

Attitude towards treatment, side-effects, mental state and quality of life was assessed in 53 chronic schizophrenic out-patients on maintenance treatment with depot neuroleptics. It was found that 60% of the patients viewed depot medication positively, while only 8% viewed it negatively. Only 70% of patients complained about side-effects, even though 94% had scored as having them. Hypokinesia and hyperkinesis were the side-effects least noticed by the patients, but most noticed by the treating physician, while the opposite was the case with psychic side-effects. Only 49% of patients thought they had a psychotic illness, and there was no correlation between the patients' own evaluation of the severity of their illness and their score on the Positive and Negative Symptom Scale (PANSS) or the treating physician's evaluation. Quality of life did not correlate with either side-effect score or PANSS score. The schizophrenic patients' assessment of their condition was therefore in general different both from that of the treating physician and from that determined using rating scales.

A long-term cross-over pharmacokinetic study comparing perphenazine decanoate and haloperidol decanoate in schizophrenic patients.

The purpose of the study was to investigate clinical and pharmacokinetic parameters concerning perphenazine decanoate (PD) and haloperidol decanoate (HD) with an interval of 3 weeks during a study period of 51 weeks. This was done by using the available drug preparations in chronic schizophrenic patients in a randomised, double-blind, cross-over, multicentre study. In addition, an elimination phase of 6 weeks was added, when no IM injections of the depot drugs were given. Twenty-nine patients in a stable neuroleptic maintenance phase entered the study. The patients were rated during the trial according to the CPRS-SCHZ and CGI scales, the UKU side effect scale and serum concentrations of the drugs and prolactin were monitored. There was no significant difference between the drugs in antipsychotic efficacy or side effects. Thus, the doses were equipotent with regard to the CPRS-SCHZ scores. However, the patients' global improvement rating was higher for PD (52%) than for HD (39%) (P > 0.05). The elimination of both drugs was very slow. No interaction effects between PD and HD were observed. The serum levels of HD were in most patients lower than those recommended for acute-subacute treatment. The mean doses were 117 mg (0.29 mmol), range 20-313 mg PD and 120 mg (0.32 mmol), range 20-350 mg HD. The serum concentrations in nmol/L of perphenazine and haloperidol (week 24) were 0.8-15.9 and 2.3-46.7, respectively.