A randomized clinical trial of haloperidol decanoate and fluphenazine decanoate in the outpatient treatment of schizophrenia

We carried out an 8-month double-blind clinical trial comparing haloperidol decanoate with fluphenazine decanoate in the maintenance treatment of 72 schizophrenic outpatients. A parallel-groups design was used with stratification by sex and injection interval (2, 3, or 4 weeks). The initial injection interval was based on pretrial maintenance treatment with fluphenazine esters. The dosage equivalency of haloperidol decanoate (1.5 cc or 75 mg) to fluphenazine decanoate (1 cc or 25 mg) used was 3:1. This remained approximately the same throughout a 2-month titration period with a flexible dose regimen, and a further 6-month period with a fixed dose regimen. No statistically significant differences in therapeutic effect were found between the drugs. Both drugs had a similar profile for drug-induced parkinsonism, but there was a trend for differences in masking tardive dyskinesia. Haloperidol and prolactin plasma concentrations were well correlated with dosage, with the exception of haloperidol concentrations in patients receiving injections at 2-week intervals.     

Long-acting injectable risperidone: safety and efficacy in stable patients switched from conventional depot antipsychotics

Long-acting injectable risperidone was assessed in schizophrenia patients who were symptomatically stable on conventional depot antipsychotics and who were then switched to long-acting risperidone. Participants in this open-label, multicentre, 12-week trial had received flupenthixol decanoate, fluphenazine decanoate, haloperidol decanoate, or zuclopenthixol decanoate for 4 months or longer. Each was considered symptomatically stable by investigators. After receiving two cycles of their conventional depot antipsychotic during the run-in period, patients were switched to receive long-acting risperidone every 2 weeks for 12 weeks at an initial dose of 25 mg. This dose could be increased in 12.5-mg increments at 4-week intervals. Ninety-two percent of the patients received all six injections; 62% received the 25-mg dose throughout the treatment period. Adverse events related to movement disorders were reported in 3%. Severity of movement disorders decreased during long-acting risperidone treatment. Positive and Negative Syndrome Scale (PANSS) total and factor scores and scores on the Clinical Global Impressions severity scale were significantly reduced during treatment; 48% of these stable patients showed further symptom improvement (> or =20% decrease in PANSS score at endpoint). The results indicate that patients with schizophrenia who are symptomatically stable during treatment with a conventional depot antipsychotic can be safely and effectively switched to long-acting injectable risperidone without a prior transition to oral risperidone.     

Pharmacokinetics of haloperidol and fluphenazine decanoates in chronic schizophrenia

In a double-blind comparison of haloperidol decanoate and fluphenazine decanoate given 4-weekly for 60 weeks as maintenance therapy in 38 chronic schizophrenic in-patients, plasma haloperidol, fluphenazine and prolactin levels were measured at regular intervals by radioimmunoassay. After the first injection, the mean plasma haloperidol level was highest at week 1 and fell gradually towards week 4. Mean pre-dose haloperidol levels changed little after week 8. Results suggested an absorption half-life of 4 weeks, although, in three cases steady state was only achieved after 11 monthly injections. Steady state levels of both haloperidol and fluphenazine correlated highly with dose. In two subgroups observed at steady state, both drugs produced a biphasic pattern of plasma drug concentration between injections, a rapid rise on day 1 followed by stable elevated levels and a gradual return to pre-injection concentration by the end of week 4. In the fluphenazine subgroup there was a second peak on day 7 and a steeper decline, so that the mean area-under-curve in week 4 was 64% of that in week 1. Drug injections at steady state induced an increase in prolactin secretion in all of the fluphenazine sub-group and in half of those receiving haloperidol. Plasma prolactin changes resembled those for drug concentrations, but differences in times of peaks on day 1 resulted in weak correlations. Fluphenazine appeared more potent than haloperidol in provoking prolactin secretion.     

Childhood physical abuse,non-suicidal self-harm and attempted suicide amongst regular injecting drug users

Background

Childhood physical abuse (CPA), non-suicidal self-harm and attempted suicide are all highly prevalent amongst injecting drug users (IDU). This paper reported on the association of CPA with self-harm and attempted suicide.

Methods

Cross-sectional study, with 300 IDU administered a structured interview examining the prevalence of CPA, non-suicidal self-harm and suicide attempts.

Results

CPA was reported by 74.3%, and severe CPA by 40.3%. A history of non-suicidal self-harm was reported by 23.7%, and 25.7% had attempted suicide. Non-suicidal self-harm preceded the suicide attempt in 83.3% of cases where both had occurred. Independent correlates of non-suicidal self-harm were: female gender (OR 3.62), avoided home due to conflict (OR 2.28) and more extensive polydrug use (OR 1.32). Independent correlates of attempted suicide were: severe CPA (OR 3.18), frequent CPA (OR 2.54), avoided home due to conflict (OR 3.95), female gender (OR 2.99), a positive screen for Conduct Disorder (OR 3.53), and more extensive polydrug use (OR 1.52).

Conclusions

Those presenting to treatment agencies are highly likely to have a history of CPA, that may still influence their behaviours. Screening for histories of CPA and non-suicidal self-harm appears warranted when determining suicide risk for this population. At the population level, reductions in the rate of CPA, could possibly reduce the rate of subsequent suicidality.     

Deliberate self-harm in alcohol and drug misusers: patient characteristics and patterns of clinical care

The aims of this study were to describe the characteristics of alcohol and drug misusers presenting to a general hospital following suicide attempts and to investigate the patterns of clinical care they received before and after the attempts. The Oxford Monitoring System for Attempted Suicide and patient case-notes were used to obtain information on alcohol and drug misusers assessed by the general hospital psychiatric services after deliberate self-harm in 1992. Of 724 patients, 200 (28%) were substance misusers (36% of males, 23% of females). Both alcoholics and drug misusers were more likely than other attempters to be male, have histories of personality disorder and criminal offences and to make repeat attempts, and the drug misusers were more likely to be living alone and unemployed. These are characteristics associated with particularly high risk of suicide. A large proportion of the substance misusers had received specific treatment for their misuse before their attempts and the majority were offered this afterwards. Over a quarter did not accept the care they were offered. The general hospital management of attempted suicide patients must include systematic assessment for evidence of alcohol and drug misuse and maintain close links with substance misuse services. Patients identified as having problems in the use of alcohol without having developed dependence and/or physical symptoms are a group that warrants specific attention. Audits should be conducted in general hospitals to ensure that sufficient attention is being paid to the detection and management of suicide attempters with substance misuse.     

Fluphenazine decanoate maintenance in schizophrenia: a retrospective study.

In a mirror image study of 43 schizophrenic patients long-acting fluphenazine decanoate injections were found to have a significant effect in reducing hospital admissions and length of stay.     

Blood and plasma kinetics of cis(Z)-clopenthixol and fluphenazine in psychiatric patients after intramuscular injection of their decanoic esters

Whole blood and plasma concentrations of active neuroleptic drugs were measured in eight schizophrenic outpatients who had received cis(Z)-clopenthixol decanoate in Viscoleo or fluphenazine decanoate in sesame oil by intramuscular injection. Whole blood and plasma concentrations were very similar, though there was a slight tendency for blood concentrations to be higher than plasma concentrations. Maximum concentrations appeared at 1 week after administration of cis(Z)-clopenthixol decanoate, whereas the highest concentrations after fluphenazine decanoate were seen at the end of the 3-week dosage interval. Some between-individual variation and a limited within-individual variation was seen.     

Are non-fatal opioid overdoses misclassified suicide attempts? Comparing the associated correlates

This paper aimed to determine whether non-fatal opioid overdose and suicide attempts are distinct behaviours by examining the histories of 1500 opioid-dependent individuals. This paper utilised data collected as part of a large retrospective case-control study. Unintentional non-fatal opioid overdoses were more common than suicide attempts (58% vs. 32%). Overall, the correlates associated with a history of attempted suicide only and non-fatal opioid overdose only were different. Drug-related risk behaviours (including high impulsivity, injection of opioids, sedative dependence) were associated with non-fatal opioid overdose; and a history of mental disorders (depression, anxiety disorder, and screening positive for borderline personality disorder (BPD+) were associated with suicide attempts. Additionally, those who reported a history of both behaviours had a more severe clinical profile including excessive drug use, psychological disorders and childhood trauma. The study concluded that non-fatal opioid overdose and attempted suicide are distinct clinically significant problems that require different approaches for prevention. Additionally, if both behaviours are reported a thorough assessment of underlying comorbid problems should be initiated by treatment services.     

Plasma levels of neuroleptic in patients receiving depot fluphenazine

Depot forms of fluphenazine are frequently used in the outpatient treatment of psychiatric patients. To gather relevant data on pharmacokinetic characteristics of depot fluphenazines, the authors measured plasma levels of neuroleptic activity in 76 clinic patients on stable dosage regimens of fluphenazine decanoate or fluphenazine enanthate. Dose and plasma neuroleptic activity level were highly correlated for both forms of depot fluphenazine. Furthermore, the slope of the regression of log dose to the log plasma neuroleptic activity was the same for both drug forms. However, doses of enanthate twice those of decanoate were associated with the same mean plasma level of neuroleptic activity. Finally, while blood levels of drug overlapped markedly in cohorts of patients receiving different doses of depot medication, the assumption of recent studies that, on the average, patients in such cohorts have different blood and tissue levels of drug was confirmed.     

Long-term alprazolam use: abuse, dependence or treatment?

Concern about persistent benzodiazepine use should be informed by data about reasons for such use. Consecutive long term alprazolam users (n = 25) admitted to an advertised outpatient program for discontinuation were characterized with respect to alprazolam use patterns and lifetime and current Axis I and II disorders. Patient characteristics were: females 50 percent; mean age, 46 +/- 12 yrs; prior medication use--benzodiazepines, 47 percent, antidepressants, 23 percent; median duration of use 104 +/- 96 wks; median daily dose, 0.5 mg; continued effectiveness of alprazolam 50 percent. Over the duration of use patients shifted their initial pattern of use from as prescribed to a self-controlled "as required" basis (p less than .05). Interviews using the Structured Clinical Interview for DSM-III-R (SCID) yielded diagnoses of DSM-III-R alprazolam dependence in all patients plus at least one additional psychiatric diagnosis in 65 percent (Axis I 65%; Axis II 39%). Most persistent alprazolam use does not represent abuse or addiction as usually understood. These data are most consistent with the interpretation that alprazolam is the most recent benzodiazepine used by patients to help control clinically important psychopathology and that most users make efforts to control or stop use.     

Single-dose pharmacokinetics of fluphenazine after fluphenazine decanoate administration

Fluphenazine decanoate is commonly used as part of maintenance treatment of schizophrenia, but its pharmacokinetics are poorly understood. We administered a single intramuscular dose of fluphenazine decanoate to nine patients and found that plasma fluphenazine level did not decline to 50% of the peak level by day 26 in any of the patients. This means that it has a long half-life measurable in months rather than weeks.     

Plasma prolactin and fluphenazine concentrations in patients receiving fluphenazine decanoate: stability over injection intervals

Plasma prolactin and fluphenazine concentrations were measured in a group of 17 patients (9 males, 8 females) with schizophrenia who were receiving chronic treatment with fluphenazine decanoate. Neither measure was significantly correlated with clinical effect, as measured by the Brief Psychiatric Rating Scale, at any of the 5 pre-injection times examined. None of the measures showed statistically significant (P greater than 0.05; MANOVA) variations with time. Neither measure showed a significant correlation with the dose (expressed as mg/kg) of fluphenazine. The implications of the study for monitoring chronic treatment of schizophrenia are discussed.     

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.     

Clinical pharmacokinetics of the depot antipsychotics

The clinical pharmacokinetics of the 4 depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, clopenthixol decanoate and flupenthixol decanoate) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. The depot antipsychotics are synthesised by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. Fluphenazine is available as both an enanthate and decanoate ester (both dissolved in sesame oil), although the decanoate is more commonly used clinically. The enanthate produces peak plasma concentrations on days 2 to 3 and declines with an apparent elimination half-life (i.e. the half-time of the apparent first-order decline of plasma concentrations) of 3.5 to 4 days after a single injection. The decanoate produces an early high peak which occurs during the first day and then declines with an apparent half-life ranging from 6.8 to 9.6 days following a single injection. After multiple injections of fluphenazine decanoate, however, the mean apparent half-life increases to 14.3 days, and the time to reach steady-state is 4 to 6 weeks. Withdrawal studies with fluphenazine decanoate suggest that relapsing patients have a more rapid plasma concentration decline than non-relapsing patients, and that the plasma concentrations do not decline smoothly but may exhibit 'lumps' due to residual release from previous injection sites or multicompartment redistribution. Cigarette smoking has been found to be associated with a 2.33-fold increase in the clearance of fluphenazine decanoate. In 3 different studies, fluphenazine has been proposed to have a therapeutic range from less than 0.15 to 0.5 ng/ml with an upper therapeutic range of 4.0 ng/ml. Plasma concentrations following the decanoate injection are generally lower than, but clinically equivalent to, those attained with the oral form of the drug. Haloperidol decanoate plasma concentrations peak on the seventh day following injection although, in some patients, this peak may occur on the first day.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative enzyme-inducing effects of chlorpromazine and fluphenazine therapies in psychotic patients

Antipyrine elimination kinetics were measured in psychotic patients receiving either long-term chloropromazine or fluphenazine decanoate therapy and in non-medicated control subjects. Patients receiving chlorpromazine metabolised antipyrine faster than the controls while, in patients receiving fluphenazine decanoate, there was no change. The results suggest that long-term chlorpromazine therapy induced the activity of drug-metabolising enzymes, whereas fluphenazine decanoate therapy had no effect.     

Acquisition and retention of skills training methods in chronic schizophrenic outpatients.

Forty-one DSM-III-R schizophrenic subjects on constant, low-dose maintenance neuroleptic drug therapy (5-10 mg of fluphenazine decanoate intramuscularly every 2 weeks) were randomly assigned to structured and modularized skills training or to supportive group psychotherapy. The skills training was designed by using cognitive and behavioral methods to compensate for the learning disabilities that plague many schizophrenic patients. Skill acquisition was assessed by using quantified performance on standardized role-play tests. Subjects who received skills training made significant gains in each of the areas taught, whereas those who participated in the control psychotherapy group did not. The knowledge and skills learned during training were retained without significant erosion over a 1-year followup period. These results suggest that the use of structured principles of learning and cognitive therapy can effectively train schizophrenics in skill areas pertinent to the self-management of their illness.     

Positive and negative symptoms, depression and social disability in chronic schizophrenia: a comparative trial of bromperidol and fluphenazine decanoates.

A 1 year double-blind trial of bromperidol decanoate and fluphenazine decanoate was conducted in the maintenance treatment of 47 outpatients with schizophrenia. Six patients relapsed on bromperidol decanoate and none on fluphenazine decanoate, a difference which is statistically significant. No significant differences in positive and negative symptoms, nor depression measures were found between treatment groups when comparisons were made for change in score from entry to last visit. However, patients on fluphenazine decanoate achieved significantly better changes on social disability (Morningside scale) compared to those on bromperidol decanoate. The incidence of extrapyramidal side-effects was similar in both groups, and no statistically significant differences emerged in body weight change between treatments.     

Suicide Attempt Histories in Alcohol-Dependent Men: Differences in Psychological Profiles

Fifty-three alcohol-dependent men without additional Axis I disorders were divided into two groups based on past history of suicide attempts (SP = suicide positive, N = 15; SN = suicide negative, N = 38). Post-hoc analysis revealed that the two groups were matched for age, racial makeup, family history of suicide, and total number of years of drinking. A significantly higher percentage of SP group patients had personal and family histories of either illicit drug use, past psychiatric treatment, or both. Psychological profiles demonstrated exaggerated tendencies toward sociopathy, attitudinal deviance, heightened activity, anxiety, depression, hostility, and disordered thinking among the SP patients. These findings highlight the importance of designing individualized relapse prevention programs.     

Serum neuroleptic levels and clinical outcome in schizophrenic patients treated with fluphenazine decanoate

Serum neuroleptic levels were measured by radioreceptor assay in 24 schizophrenic patients maintained on fluphenazine decanoate. Clinical state was assessed at the time of neuroleptic level measurement and during the subsequent 6 months. Patients with persistent psychotic symptoms were on higher doses of fluphenazine decanoate than those in remission and had higher neuroleptic levels. Patients who relapsed during the 6 months after neuroleptic levels were measured did not differ in dose from those who stayed in remission but tended to have lower serum neuroleptic levels. These observations suggest that persistent psychotic symptoms in neuroleptic-maintained patients cannot be accounted for solely by inadequate treatment. Furthermore, in remitted patients serum neuroleptic levels may be a determinant of outcome.     

Plasma fluphenazine concentrations in outpatients receiving fluphenazine decanoate (Modecate)

Plasma fluphenazine concentrations were measured by neuroleptic radioreceptor assay in 17 outpatients receiving chronic treatment with intramuscular fluphenazine decanoate. The range of concentrations was 0.5–2.4 μg/L over the dosage range of 0.30–3.2 mg/d. Age, sex and smoking status had no influence on plasma fluphenazine concentrations, which were not correlated with dose (expressed as mg/kg/d). There was no significant correlation between plasma concentration and clinical status of the patients. No difference in plasma concentration between patients with extrapyramidal signs or tardive dyskinesia and those without signs were observed.