A 15-year open study on a cohort of West-African out-patients with a chronic psychosis

BACKGROUND: We wanted to find out if the additional costs of depot neuroleptic in comparison to oral medication was justified by a decrease in admission days. METHODS: An open study on a cohort of chronic psychotic out-patients (n=45) consisting of a retrospective 10-year period on oral medication followed by a prospective 5-year period of treatment with haloperidol decanoate. After recording socio-demographic characteristics and a DSM-III-R diagnosis, patients were assessed before and after the administration of depot neuroleptic with the BPRS, the NOSIE, the SDRS and a list of side effects. A semi-structured interview was conducted with the patients and their families to ask about the change in social relationships with family members and other people after starting the depot treatment. Social intervention was limited to involvement of the family in the monthly depot medication outpatient clinic and to an explanation of the rationale of follow-up treatment and deinstitutionalisation of psychiatric care in the village of origin. RESULTS: The number of admission days decreased from an average of 100 days a year on oral medication to 5 days a year on depot neuroleptic. Patients report a sharp decrease in symptoms paralleled by an increase in social functioning over the first 3 months. After 6-9 months this pattern stabilised and was maintained over the period from 1 to 5 years whereas the dosage was further decreased to an average of 1 cc decanoate or 20 haldol equivalents monthly. CONCLUSIONS: This study suggests that depot neuroleptic in the context of a public mental health approach is a highly effective and feasible treatment for West African patients suffering from a chronic functional psychosis.     

Comparative efficacy of long-acting depot and oral neuroleptic medications in preventing schizophrenic recidivism

Two health service data bases provided data on the use of neuroleptic medications in the maintenance therapy of schizophrenic patients in the Canadian province of Saskatchewan. The pattern of prescribing medication appeared to be influenced by the bed-to-population ratio. For 1235 discharged schizophrenic patients, the 2-year rehospitalization rate (56%) was higher than expected. Although oral maintenance therapy predominated, patients maintained on long-acting depot neuroleptic medication had a significantly lower (p less than .05) rehospitalization rate than those on oral preparations. The highest rehospitalization rate was found among patients prescribed combined depot and oral preparations, confirming the ineffectiveness of combined medication. Using data bases avoided the sampling bias inherent in prospective controlled trials and provided a complementary epidemiologic dimension to the study of maintenance neuroleptic therapy of schizophrenia under normal treatment conditions.     

Which factors affect treatment response in late paraphrenia?

Sixty-four patients with late paraphrenia who had been prescribed neuroleptic treatment for at least three months in the previous year were clinically reviewed in order to asses their treatment response. At the time of assessment, 42.2% of the patients showed no response, 31.3% a partial response and 26.6% a full response to treatment. Compliance with medication, receiving depot rather than oral medication, and use of a community psychiatric nurse if the patient was an outpatient all had a positive effect on treatment response. Despite their better treatment response rate, patients prescribed depot medication received on average a lower daily dose in chlorpromazine equivalents than those prescribed oral medication. Improved compliance, greater clinical efficacy and a reduction in the dose of neuroleptic medication administered are all good reasons to commence treatment of late paraphrenia with a depot antipsychotic medication.     

The duration of maintenance therapy in chronic schizophrenia.

The incidence of relapse was compared between two groups of chronic schizophrenic patients (mean duration periods 19 months and 29.5 months) discontinuing depot neuroleptic injections, and matched controls remaining on depot injections. The results show a higher relapse rate in patients discontinuing injections, significant at the 1% level, in both groups. The proportion of patients improving upon resumption of depot injections confirms the importance of this form of medication in comparison to prescribed oral medication. The results strongly suggest that there is a significant therapeutic gain in continuing maintenance therapy with depot neuroleptic injections for a minimum period of 3 years after the last relapse in a substantial proportion of chronic schizophrenic patients.     

Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia.

This review covers some recent work on: 1. The effects of route of administration on the pharmacokinetics of fluphenazine and some of its metabolites; 2. The clinical pharmacokinetics of fluphenazine in acute patients medicated with oral fluphenazine; 3. The clinical pharmacokinetics of haloperidol in acute patients medicated with oral haloperidol; 4. The clinical pharmacokinetics of fluphenazine in the maintenance of individuals with chronic schizophrenia with fluphenazine decanoate; 5. A systematic dose reduction study in maintenance treatment refractory patients with oral haloperidol. A study in which plasma levels of fluphenazine and fluphenazine sulfoxide were measured in a group of DSM-III-R patients with schizophrenia before and after switching from oral fluphenazine to depot fluphenazine, decanoate revealed much higher levels of fluphenazine sulfoxide with oral medication compared with those found with depot fluphenazine. These data illustrate the effect of "first pass" metabolism after oral fluphenazine. Thus in a group of 33 patients randomly assigned to receive 5 mg, 10 mg or 25 mg oral fluphenazine daily, steady state plasma fluphenazine levels at each dose were significantly lower that those of fluphenazine sulfoxide or 7-hydroxy-fluphenazine, although there were no significant differences between the levels of fluphenazine and fluphenazine N4-oxide. On the other hand, plasma levels of the parent drug were significantly higher than those of any metabolite in a corresponding group of patients at steady state on depot medication. These observations underscore the importance of route dependent differences in the pharmacokinetics of fluphenazine which can lead to problems when switching patients from oral to depot neuroleptics. The concept of "disabling side-effects" is an important development in understanding relationships between plasma levels of neuroleptic drugs and clinical response in patients with schizophrenia. Risk-benefit analysis shows clearly that evaluation of relationships between plasma levels and clinical response must take into account the consequences of side-effects which the patient feels have a negating effect on therapy. Emerging data on putative therapeutic plasma level ranges in maintenance therapy are potentially important and may be particularly useful in the maintenance of patients on low dose therapy. It is noteworthy that in a carefully executed dose reduction study in treatment resistant patients under medication with haloperidol, the mean lowest effective dose (8.7 ng/mL) lay within the optimal therapeutic range (5 ng/mL to 12 ng/mL) found in acutely psychotic patients. The study showed that gradual dose reduction of neuroleptic was possible in chronic treatment resistant patients with schizophrenia who were originally thought by ward staff to require high doses of neuroleptic.(ABSTRACT TRUNCATED AT 400 WORDS)     

Depot neuroleptic therapy: an underutilized treatment option.

BACKGROUND: Depot neuroleptics are effective as long-term maintenance therapy in chronic schizophrenia and are widely used in Europe. In the United States, however, physicians have been reluctant to use them. They assume that depot neuroleptics present an increased risk of major side effects, that patients do not accept or tolerate them as well as oral agents, and that prescribing depot neuroleptics increases the possibility of medicolegal problems. METHOD: We analyzed the published data on neuroleptic malignant syndrome, tardive dyskinesia, extrapyramidal symptoms, perceptions of depot therapy, and medicolegal concerns. Whenever possible, we used the Mantel-Haenszel test to compare the outcome of oral versus depot neuroleptic medication treatment. RESULTS: Depot neuroleptics are not associated with an increase in any of the negative outcomes assessed. CONCLUSION: Depot neuroleptics represent a valuable treatment option for many patients and merit wider use.     

Group therapy with schizophrenic patients in outpatient departments

Twelve schizophrenic patients were treated with neuroleptic drugs and psychoanalytically oriented group therapy during a period of 2 years. Twelve other patients, matched with regard to the state of their disease, sex, age, civil status and social situation, were given neuroleptic drugs and contact therapy during the same period. All patients were evaluated by the same test procedures. The Rorschach test, the Defence Mechanism Test (DMT), interviews and a self-evaluation test, were performed before and after 2 years of treatment. The dates of discharge, number of days in hospital and neuroleptic drugs prescribed were recorded for all patients over a 2-year period before, during and after treatment. Half of the patients improved, regardless of the treatment they received. No evaluation instrument used before the start of treatment could predict the patients who later improved. After 2 years of treatment, it was assessed that the patients who improved required a further period of insight therapy.     

Neuroleptic exposure in bipolar outpatients in a research setting

The study purpose was to determine the extent of neuroleptic exposure in bipolar outpatients maintained on mood-stabilizing medications and any clinical correlates associated with this exposure. Data on medication and severity of illness were gathered from the records (prospective and retrospective) of 70 bipolar patients involved in outpatient research studies at the National Institute of Mental Health (NIMH). The percentage of patients requiring neuroleptic treatment, percentage of time on neuroleptics during the period of observation, total dose of neuroleptics in chlorpromazine (CPZ) equivalency, and number of neuroleptic trials were among the variables calculated. Regression analyses and analyses of variance (ANOVAs) were performed to assess the relationships between neuroleptic exposure and clinical course. Forty-five patients (64.3%) had a neuroleptic trial during the prospective study. Subjects exposed to neuroleptics spent, on average, 15.4% (median, 6.0%) of the time in study on neuroleptic treatment, and were administered, on average, a total of 11,770.5 mg (median, 1,621.9 mg) of neuroleptics (in CPZ equivalency) per year in the prospective study. As expected, bipolar I compared with bipolar II patients had significantly higher neuroleptic exposure by a number of measures. The number of hospitalizations for mania prior to study entry was associated with greater prospective neuroleptic use during the study. Despite maintenance treatment with one or more moodstabilizing agents, we found a relatively high need for adjunctive neuroleptic medication even in this sample of high-functioning bipolar outpatients. These results highlight the need for the study of alternatives, as well as more effective primary mood-stabilizing agents.     

Neuroleptic withdrawal with remitted schizophrenics: a naturalistic follow-up study

Despite proven efficacy of maintenance pharmacotherapy in schizophrenia, indefinite neuroleptic treatment may not be optimal for all patients. It is uncertain how long maintenance therapy should be continued and how to identify those patients who can withdraw eventually from neuroleptics. Prospective randomized controlled studies are the ideal approach for evaluation of medication, however they are inevitably for the short term and may not be suitable for addressing the above-mentioned issue. In this study, we naturalistically followed up 30 remitted schizophrenics for 10.7 years on average and examined factors that might affect the outcomes. Of 30 remitted patients, 8 cases (26.7%) ceased neuroleptic use completely for more than 2 years. The details of clinical courses of those 8 cases were described as case reports in this report. Importantly, 4 of 8 withdrawal cases required 2 or more trials in order for neuroleptic withdrawal to reach a drug-free state. Factors which significantly affected successful withdrawal involved the mode of onset and the ages at first neuroleptic withdrawal trial. Our results suggest that approximately one-fourth of completely remitted patients could withdraw neuroleptics, but certain cases may need withdrawal trials at least a few times to accomplish the drug-free state.     

Recent developments in the care, treatment, and rehabilitation of the chronic mentally ill in Britain

Just as the deinstitutionalization movement has swept the United States in recent years, the effort to provide alternatives to public hospitals has been government policy in Britain for the past 20 years. While problems remain, Britain, which reduced its mental hospital census less than America, has had some success in finding proper community treatment and care for its former hospital patients, especially the chronically disabled. The author describes recent developments in the administration and organization of services for chronic patients and in clinical practice. The effects of new legislation and several government reports on community care are outlined, as are two new experiments in finding community housing for former hospital patients. Developments in biological psychiatry, use of depot neuroleptic therapy, electroconvulsive therapy, and industrial therapy are also briefly mentioned.     

Blood biogenic amines during clozapine treatment of early-onset schizophrenia

Summary The aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14–22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 ± 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11–20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n=7) and nonresponders (n=8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therapeutic actions of the atypical neuroleptic clozapine.     

First vs multiple episode schizophrenia: two-year outcome of intermittent and maintenance medication strategies.

Results of studies on intermittent neuroleptic treatment strategies in first episode (FE) schizophrenia have not been published. Aims of the present study were to elucidate the comparative efficacy of prodrome-based neuroleptic intervention in first vs multiple episode (ME) schizophrenia. As to the methods, three randomly assigned open neuroleptic treatment strategies were compared over 2 years in 363 schizophrenic outpatients (115 FE, 248 ME; ICD-9, RDC): maintenance medication vs two intermittent medication strategies (prodrome-based intervention and crisis intervention). Concerning relapse prevention, the results demonstrate that ME patients seemed to profit most from maintenance medication compared to both intermittent treatments, whereas FE patients did equally well under maintenance medication and prodrome-based intervention treatment. Psychopathology, social adjustment, subjective well-being, and side-effects after two years did not differ significantly between the FE and ME patients irrespective of treatment strategy. Concerning treatment adherence, FE patients complied better with prodrome-based intervention than with maintenance medication. Cumulative neuroleptic dosage was lowest in FE patients under intermittent treatment. In conclusion, maintenance medication is the best strategy for relapse prevention in ME patients. In FE patients, prodrome-based intermittent intervention seems to be equivalent or even better with respect to compliance and dosage applied.     

Four-year outcome in non-compliant schizophrenia patients treated with or without home-based ambulatory outpatient care.

Non-compliance in neuroleptic maintenance treatment is a major concern in schizophrenia. Home-based outpatient care has been shown both to improve medication compliance and reduce relapse frequency. We analysed the need for hospitalisation, levels of functioning and mortality rate during the de-institutionalisation process in 41 schizophrenia patients with repeated hospitalisations and prolonged history of non-compliance. Eighteen of the patients received ambulatory outpatient care (AOC) after discharge. This treatment procedure focuses on enduring neuroleptic maintenance treatment. One of the hospital nurses takes care of home visits every 2-4 weeks. In the 4-year follow-up, half of the patients in the AOC group did not need hospitalisation at all and the number of days of hospitalisation in the whole group diminished by almost four-fifths compared with the previous 4 years. In the non-AOC group, there was a more limited decrease in the number of days of hospitalisation during the corresponding follow-up period. The mortality rates showed a slight tendency towards a better outcome in the AOC group. There was no change in the levels of functioning in the AOC group. This treatment can be carried out with limited resources. It clearly reduces the need for hospitalisation in a subgroup of schizophrenia patients having problems with compliance and recurrent relapse. The effectiveness of AOC on the mortality rates of schizophrenia patients needs further examination.     

Depot neuroleptic medication and serum levels by radioreceptor assay: prolactin concentration, electrocardiogram abnormalities and six-month outcome

Twenty-six chronic schizophrenic patients on well-established depot neuroleptic regimes with stable doses (16 on fluphenazine decanoate, 10 on flupenthixol decanoate) had serum neuroleptic levels measured by radioreceptor assay (RRA) and were followed for six months. The serum prolactin (PRL) concentration and resting electrocardiogram (ECG) were also taken at the beginning of the study period. Correlations had previously been noted between RRA measured neuroleptic levels and outcome in both acute and chronic patients on oral medication. However, in this study of depot medication no significant correlations were found between serum neuroleptic concentration, serum prolactin concentration and the clinical state or outcome. The prevalence (33%) and type of ECG abnormality observed was similar to that previously reported.     

Adaptive and Maladaptive Regression in Hemodialysis

Abstract

Despite proven efficacy of maintenance pharmacotherapy in schizophrenia, indefinite neuroleptic treatment may not be optimal for all patients. It is uncertain how long maintenance therapy should be continued and how to identify those patients who can withdraw eventually from neuroleptics. Prospective randomized controlled studies are the ideal approach for evaluation of medication, however they are inevitably for the short term and may not be suitable for addressing the above–mentioned issue. In this study, we naturalistically followed up 30 remitted schizophrenics for 10.7 years on average and examined factors that might affect the outcomes. Of 30 remitted patients, 8 cases (26.7%) ceased neuroleptic use completely for more than 2 years. The details of clinical courses of those 8 cases were described as case reports in this report. Importantly, 4 of 8 withdrawal cases required 2 or more trials in order for neuroleptic withdrawal to reach a drug–free state. Factors which significantly affected successful withdrawal involved the mode of onset and the ages at first neuroleptic withdrawal trial. Our results suggest that approximately one-fourth of completely remitted patients could withdraw neuroleptics, but certain cases may need withdrawal trials at least a few times to accomplish the drug–free state.     

Reducing the dose of depot neuroleptics in stable schizophrenia.

In order to determine the safety of reducing maintenance neuroleptic dose in long-term ambulatory schizophrenia, a step-wise depot reduction study was carried out on patients over a six month period. Doses were reduced by 1/8 of original approximately every two months for a total of three reductions. At the end of dose reduction and at six month follow-up, relapse rate was calculated. Relapse in this study was defined as the clinical decision to either increase neuroleptic dose or to hospitalize. Approximately 50% of the patients relapsed. There was no association with life events as measured by the Paykel scale. Where relapse occurred, it was usually seen subsequent to the second dose reduction. Patients who survived dose reduction had been maintained for a significantly longer period on depot neuroleptics and tended to suffer from a form of schizophrenia which required the co-administration of antidepressants. The findings show that, for a population on long-term depot medication, the risk of symptom exacerbation after gradual step-wise neuroleptic reduction is 50%. The results help to delineate which patients will fall into that 50%.     

Clinical characteristics,health beliefs and compliance with maintenance treatment: a comparison between regular and irregular attenders at a depot clinic

ABSTRACT– This study investigated the relationship between clinical characteristics, health beliefs and compliance with depot neuroleptic maintenance treatment in schizophrenic patients by comparing a group of 40 irregular clinic attenders with another group of regular attenders matched by age and sex. While the 2 groups showed no difference in drug-induced extrapyramidal effects, the former were significantly more often depressed than the latter. Test-retest reliability coefficients of a 4-section health belief questionnaire showed marked variation in individual items. The 2 groups showed no difference in their perception of past effect of illness, likelihood of a relapse if maintenance treatment was stopped and effects of maintenance treatment.     

Weight changes with depot neuroleptic maintenance therapy.

A prospective study of schizophrenic patients prescribed injectable depot neuroleptic drugs as maintenance therapy showed a clinically significant weight gain in 55% of patients. No significant difference was shown between flupenthixol decanoate and fluphenazine decanoate, nor was a clinically meaningful relationship shown with dose, or the use of anti-parkinsonian drugs. The weight gain continued for at least 2 years following a mental state relapse. It is suggested that the monitoring of weight and giving of appropriate advice on diet are two essential in maintenance therapy of chronic schizophrenia.     

Depot pipotiazine 1970-1982: a review

In the past 14 years pipotiazine palmitate, the second oldest depot neuroleptic, has proven to be effective and safe in reducing and preventing resurgence of symptoms of acute and chronic psychoses, chiefly in schizophrenia. It is particularly valuable in the management of erratic ingestors and unreliable absorbers of oral neuroleptics. Clinical experience substantiates that pipotiazine palmitate therapy is best initiated at low doses (25 mg), and that the most effective maintenance dosage is 25 to 200 mg once a month. Pipotiazine palmitate has a low propensity to evoke extrapyramidal reactions; in fact, it causes the lowest incidence of EPS of all depot neuroleptics. Patients receiving pipotiazine palmitate seldom require concomitant antiparkinsonian medication. This review highlights other assets and liabilities of depot pipotiazine therapy.     

Tardive dyskinesia in schizophrenic outpatients: prevalence and significant variables

All the patients (N = 94) of an outpatient clinic for schizophrenia were evaluated for the presence and severity of neuroleptic induced tardive dyskinesia. Fourty-four percent of the patients showed some degree of tardive dyskinesia. The proportion of patients with tardive dyskinesia increased directly with age and with number of years of neuroleptic treatment. Recent dose reduction exacerbated the syndrome. There were no gender differences in the clinic as a whole. Severity of dyskinesia correlated with anticholinergic drug use, with the piperazine/butyrophenone group of neuroleptics and with the use of depot-administered drugs. The depot correlation was highly significant in the under-30 age group.