Late Reduction of Cocaine Cravings in a Randomized, Double-Blind Trial of Aripiprazole vs Perphenazine in Schizophrenia and Comorbid Cocaine Dependence.

PURPOSE: Co-occurring schizophrenia spectrum disorder and International Statistical Classification of Diseases, 10th Revision cocaine dependence present a particularly destructive constellation that is often difficult to treat. Both conditions raise dopamine transmission effects in the brain. Traditional neuroleptics block dopamine receptors, whereas aripiprazole modulates dopamine activity as an agonist/antagonist. We tested whether dopamine modulation is superior to dopamine blocking in dual-diagnosis patients. METHODS: In a randomized, double-blind, comparison design, cocaine-dependent schizophrenic subjects actively using cocaine received either aripiprazole or perphenazine in an 8-week trial. Primary outcome targeted cocaine-free urine sample proportions, whereas cocaine craving scores were a secondary variable. RESULTS: Subjects (N = 44) randomized (n = 22 per group) did not differ at baseline. The proportion of cocaine-free urine samples did not differ by medication group. Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5-point subscales, craving intensity decreased by 1.53 ± 0.43 (P < 0.0005) points, craving frequency by 1.4 ± 0.40 (P > 0.0004) points, and craving duration by 1.76 ± 0.44 (P > 0.0001) points. CONCLUSIONS: A drug effect of aripiprazole on craving items appeared at week 6 of treatment, on average, and was not seen before that length of drug exposure. The data suggest that dopamine modulation reduces cocaine cravings but requires an acclimation period. To understand the mechanism of action better, a trial of depot aripiprazole may be useful. Clinically, a reduction in craving potentially offers a clearer focus for ongoing behavioral treatment. It may also offer a longer-term treatment effect with respect to the severity of relapse.

Identification and management of tardive dyskinesia: A case series and literature review.

Tardive dyskinesia (TD) is a serious, disabling and potentially permanent, neurological hyperkinetic movement disorder that occurs after months or years of taking dopamine receptor-blocking agents. The pathophysiology of TD is complex, multifactorial and still not fully understood. Although there is no identified effective and standard treatment for TD, several agents have been tried for the management of this motor disturbance. The aim of this case series is to review the literature in regard to the identification, diagnosis and the treatment of TD with anticholinergics, anticholinergic medication withdrawal, cholinergic agents, botulinum toxin intramuscular injections, tetrabenazine, levetiracetam, propranolol and zolpidem, and to describe one case of TD that responded favorably to clonazepam and two cases of TD that responded favorably to Ginkgo biloba.

Randomized Trial of the Effect of Four Second-Generation Antipsychotics and One First-Generation Antipsychotic on Cigarette Smoking, Alcohol, and Drug Use in Chronic Schizophrenia.

No large-scale randomized trial has compared the effect of different second-generation antipsychotic drugs and any first-generation drug on alcohol, drug and nicotine use in patients with schizophrenia. The Clinical Antipsychotic Trial of Intervention Effectiveness study randomly assigned 1432 patients formally diagnosed with schizophrenia to four second-generation antipsychotic drugs (olanzapine, risperidone quetiapine, and ziprasidone) and one first-generation antipsychotic (perphenazine) and followed them for up to 18 months. Secondary outcome data documented cigarettes smoked in the past week and alcohol and drug use severity ratings. At baseline, 61% of patients smoked, 35% used alcohol, and 23% used illicit drugs. Although there were significant effects of time showing reduction in substance use over the 18 months (all p < 0.0001), this study found no evidence that any antipsychotic was robustly superior to any other in a secondary analysis of data on substance use outcomes from a large 18-month randomized schizophrenia trial.

Perphenazine for schizophrenia.

BACKGROUND: Perphenazine is an old phenothiazine antipsychotic with a potency similar to haloperidol. It has been used for many years and is popular in the northern European countries and Japan. OBJECTIVES: To examine the clinical effects and safety of perphenazine for those with schizophrenia and schizophrenia-like psychoses. SEARCH METHODS: We updated our original search using the Cochrane Schizophrenia Group's register (September 2013), references of all included studies and contacted pharmaceutical companies and authors of included studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials that compared perphenazine with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. We excluded trials of depot formulations of perphenazine. DATA COLLECTION AND ANALYSIS: Two review authors independently inspected citations and, where possible, abstracts. We ordered papers, inspected and quality assessed them. We extracted data, again working independently. If loss to follow-up was greater than 50% we considered results as 'prone to bias'. For dichotomous data, we calculated risk ratios (RR) and for continuous data we calculated mean differences (MD), both with the 95% confidence intervals (CI). We assessed quality of data using the GRADE (Grading of Recommendations Assessment, Development and Evaluationtool) and assessed risk of bias for included studies. MAIN RESULTS: Thirty-one studies fulfilled the inclusion criteria, with a total of 4662 participants (of which 4522 were receiving the drugs relevant to our comparison) and presented data that could be used for at least one comparison. The trial centres were located in Europe (especially Scandinavia), Japan and Northern America.When comparing perphenazine with placebo, for our primary outcome of clinical response, results favoured perphenazine with significantly more people receiving placebo rated as either 'no better or deterioration' for global state than people receiving perphenazine (1 RCT, n = 61 RR 0.32 CI 0.13 to 0.78, very low quality evidence). More people receiving placebo relapsed, although not a statistically significant number (1 RCT, n = 48, RR 0.14 CI 0.02 to 1.07, very low quality evidence). Death was not reported in the perphenazine versus placebo comparison. Experiences of dystonia were equivocal between groups (1 RCT, n = 48, RR 1.00 CI 0.07 to 15.08, very low quality evidence); other outcomes not reported in this comparison include serious adverse events, economic outcomes, and service use and hospitalisation.For the comparison of perphenazine versus any other antipsychotic drugs, no real differences in effect between the drugs were found. There was no significant difference between groups for those considered 'no better or deterioration' (17 RCTs, n = 1879, RR 1.04 CI 0.91 to 1.17, very low quality evidence). For mental state outcome of 'no effect' of the study drug, there was again no significant difference between groups (4 RCTs, n = 383, RR 1.24 CI 0.61 to 2.52, very low quality evidence). Death was not reported in any of the included studies. There was no significant difference in rates of dystonia with perphenazine versus any other antipsychotic drugs (4 RCTs, n = 416, RR 1.36 CI 0.23 to 8.16, very low quality evidence), nor was there a significant difference between groups for serious adverse events (2 RCTs, n = 1760, RR 0.98 CI 0.68 to 1.41, very low quality evidence). AUTHORS' CONCLUSIONS: Although perphenazine has been used in randomised trials for more than 50 years, incomplete reporting and the variety of comparators used make it impossible to draw clear conclusions. All data for the main outcomes in this review were of very low quality evidence. At best we can say that perphenazine showed similar effects and adverse events as several of the other antipsychotic drugs. Since perphenazine is a relatively inexpensive and frequently used compound, further trials are justified to clarify the properties of this classical antipsychotic drug.

Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial.

Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.

Effects of antipsychotics on bone mineral density and prolactin levels in patients with schizophrenia: a 12-month prospective study.

OBJECTIVE: Effects of conventional and atypical antipsychotics on bone mineral density (BMD) and serum prolactin levels (PRL) were examined in patients with schizophrenia. METHODS: One hundred and sixty-three first-episode inpatients with schizophrenia were recruited, to whom one of three conventional antipsychotics (perphenazine, sulpiride, and chlorpromazine) or one of three atypical antipsychotics (clozapine, quetiapine, and aripiprazole) was prescribed for 12 months as appropriate. BMD and PRL were tested before and after treatment. Same measures were conducted in 90 matched healthy controls. RESULTS: Baseline BMD of postero-anterior L1-L4 range from 1.04 ± 0.17 to 1.42 ± 1.23, and there was no significant difference between the patients group and healthy control group. However, post-treatment BMD values in patients (ranging from 1.02 ± 0.15 to 1.23 ± 0.10) were significantly lower than that in healthy controls (ranging from 1.15 ± 0.12 to 1.42 ± 1.36). The BMD values after conventional antipsychotics were significantly lower than that after atypical antipsychotics. The PRL level after conventional antipsychotics (53.05 ± 30.25 ng/ml) was significantly higher than that after atypical antipsychotics (32.81 ± 17.42 ng/ml). Conditioned relevance analysis revealed significant negative correlations between the PRL level and the BMD values after conventional antipsychotics. CONCLUSION: The increase of PRL might be an important risk factor leading to a high prevalence of osteoporosis in patients with schizophrenia on long-term conventional antipsychotic medication.

Impact of once- versus twice-daily perphenazine dosing on clinical outcomes: an analysis of the CATIE data.

OBJECTIVE: The objective of this study was to evaluate the impact of once- versus twice-daily dosing of perphenazine, which has a plasma half-life of 8-12 hours, on clinical outcomes in patients with schizophrenia. METHOD: Data from phase 1 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) conducted between January 2001 and December 2004 were used in this post hoc analysis. Patients with schizophrenia (DSM-IV) randomly allocated to treatment with perphenazine were also randomly assigned to once-daily (N = 133) or twice-daily (N = 124) dosing and followed over 18 months. Discontinuation rate and time to discontinuation were used as primary outcomes to compare the 2 groups. The following clinical outcomes were analyzed as secondary measures: efficacy-Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory and safety/tolerability-Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, and body weight. Data on treatment-emergent adverse events, concomitant psychotropic medications, and medication adherence (pill count and clinician rating scale) were also analyzed for each group. RESULTS: No significant differences were found in any outcome measures between the once-daily and twice-daily dosing groups, which remained the same when using the mean dose of perphenazine as a covariate. CONCLUSIONS: Perphenazine is routinely administered in a divided dosage regimen because of its relatively short plasma half-life. However, the present findings challenge such a strategy, suggesting that once-daily represents a viable treatment option. Results are discussed in the context of more recent evidence that challenges the need for high and continuous dopamine D2 receptor blockade to sustain antipsychotic response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00014001.

Extrapyramidal symptoms following administration of oral perphenazine 4 or 8 mg: an 11-year retrospective analysis.

BACKGROUND: Perphenazine is a treatment option in postoperative nausea and vomiting (PONV) prophylaxis. Chronic administration and high dose are known to cause extrapyramidal system (EPS) dysfunction at a frequency of 8%, but the incidence of acute EPS after a single 4 or 8 mg dose is unknown. OBJECTIVE: A retrospective analysis of patient medication billing data and departmental quality records was performed (January 2001 to 10 July 2012) to identify patients who experienced EPS dysfunction after oral perphenazine. DESIGN: A retrospective analysis. SETTING: Surgical outpatients presenting to any one of 10 hospitals in the area of Pittsburgh, Pennsylvania, USA. PATIENTS: Overall, 45 766 patients received 4 or 8 mg of perphenazine before same-day surgery. MAIN OUTCOME MEASURES: EPS dysfunction was defined as acute dystonia, akathisia or pseudoparkinsonism. Records were reviewed to determine the likely number of reactions to perphenazine, the nature of these reactions and impact on patient care. RESULTS: There were four 'likely' cases of EPS dysfunction, and two 'possible' cases. Five reported events were consistent with akathisia, with the sixth being a dystonic reaction. All six patients had resolution of symptoms, with five receiving intravenous diphenhydramine for treatment. The incidence of EPS dysfunction was 1.3 events per 10 000 patients (95% confidence interval (CI) 0.4 to 3.0, based on six events). All patients who experienced reactions pre-operatively were able to proceed to surgery without complications or delay. One patient required unplanned admission and 3-h observation owing to sedation from diphenhydramine. The incidence of EPS dysfunction after oral perphenazine is low. Reactions that did occur were mild and easily treated. CONCLUSION: Given the infrequent side effects, this single, low dose of perphenazine should be encouraged as a low-risk adjunct to any multimodal PONV prophylaxis regimen, based on the selection criteria described.

Choice of randomization to clozapine versus other second generation antipsychotics in the CATIE schizophrenia trial.

There is evidence to suggest that clozapine is underutilized in treatment-refractory schizophrenia. Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a multi-phase, randomized comparative effectiveness trial for schizophrenia, were used to identify factors associated with choosing randomization to clozapine. Two pathways were available in phase 2 of CATIE: randomization to clozapine or an untried atypical antipsychotic (2E), or randomization to an untried atypical antipsychotic (2T). We examined the proportion of entrants who chose to enter phase 2E due to the lack of efficacy of the phase 1 treatment, along with their demographic and clinical characteristics. Only 31.2% who discontinued phase 1 for lack of efficacy entered phase 2E. In multivariable analysis, males showed significantly increased odds of choosing phase 2E (adjusted odds ratio (AOR) = 2.38; confidence interval (CI) = 1.20, 4.70) as did patients with higher Positive and Negative Syndrome Scale total scores (AOR = 1.01; CI = 1.00, 1.03), more inpatient days (AOR = 1.06; CI = 1.02, 1.10) and more outpatient visits, (AOR = 1.06; CI = 1.02, 1.11). More effort examining the decision-making process of patients and providers is needed in order to increase the utilization of this effective treatment.

Social cognition and visual perception in schizophrenia inpatients treated with first-and second-generation antipsychotic drugs.

PURPOSE: Social cognition captures affect recognition, social cue perception, "theory of mind," empathy, and attributional style. The aim of our study was to assess social cognition in schizophrenia inpatients being treated with first-generation antipsychotic drugs (FGAs), n=28 (perphenazine and haloperidol, FGAs) or with second-generation antipsychotic drugs (SGAs), n=56 (olanzapine and clozapine, SGAs). SUBJECTS AND METHODS: Eighty-four patients completed the Facial Expression Recognition Test, the Voice Emotion Recognition Test, the Short Recognition Memory Test for Faces, and the Reading the Mind in the Eyes Test. Patients also completed the Visual Object and Space Perception Test (VOSP) as a control task, which would not engage social cognition. The patients were compared with fifty healthy controls matched for age and gender. RESULTS: There were no significant differences on social cognitive performance between the FGA- and SGA-treatment groups. Nor was olanzapine superior to clozapine, FGAs or both. However, patients treated with FGAs performed significantly worse on VOSP compared to both groups treated with SGAs, a 10% difference. CONCLUSIONS: We cannot conclude that SGAs were associated with better social cognition than FGAs. However, there were small but significant advantages for SGAs in non-social visual processing function, as evaluated with the VOSP.

Perphenazine suspension: a new, old treatment, side effects and continuous use.

A number of innovative delivery systems for acute antipsychotic pharmacotherapy have been developed over the years which include oral suspensions, rapidly dissolving wafers and acute intramuscular preparations. Currently, the availability of first generation antipsychotic (FGA) formulations is limited to two high potency agents: haloperidol and fluphenazine. At Yale New-Haven Psychiatric Hospital, the hospital pharmacy was able to create perphenazine suspension, a mid-potency FGA, with a record of effectiveness and tolerability that was no worse than that of second generation antipsychotics (SGAs) in the CATIE trial. In this study we compare perphenazine suspension to other first and SGAs in the risk of extrapyramidal reactions and whether or not patients were continued on the same antipsychotic they were started with at the time of discharge. Medical records of patients who received acute pharmacotherapy in a unique form while hospitalized at Yale New Haven Psychiatric Hospital from July 2009 to December 2009 were examined. All data were collected thru a chart review using a form that was created to systematically document experiences. A total of 229 patients were included in the study. There were no significant differences between treatment groups on gender, age, race or diagnosis. In the entire samples 1.75% had pseudo-parkonisnism, 1.31% had acute dystonia, 0.04% had tardive dyskinesia, 1.31% akithesia, and 4.8% any neurological side effects. There were no significant differences between agents in the likelihood of any of these side effects or of having any side effect. Higher use of anticholinergics was found in patients treated with FGAs. We also found that 77% were discharged on the same antipsychotic agent they received when they were initially hospitalized. A wide range of acute oral pharmacoptherapy in non-tablet formulations of first and SGAs should be available in psychiatric hospital formularies. FGAs seems to be as well tolerated as SGAs.

Prevalence of neuroleptic-induced restless legs syndrome in patients taking neuroleptic drugs.

Dopamine deficiency or dopamine dysfunction has been implicated as one of the factors involved in the pathophysiology of restless legs syndrome (RLS). Our objective is to determine the prevalence of primary RLS in patients taking neuroleptic drugs. One hundred patients taking neuroleptic drugs and 100 healthy age- and sex-matched controls were interviewed with the Cambridge-Hopkins diagnostic questionnaire for RLS. Patients with malignancy, end-stage renal disease, neuropathy, history of spinal cord diseases, pregnancy and Parkinson's disease were excluded. Only one patient had symptoms consistent with RLS (1%), similar to one patient in the control group. She was a 40 years old female with a diagnosis of depression. She started having RLS symptoms approximately four years after starting perphenazine. The symptoms persisted after the medications were discontinued but decreased in severity and frequency. Her serum ferritin level was 90.3 ng/ml. The prevalence of primary RLS is low in patients attending the out-patient clinic who are taking neuroleptic drugs. Other factors apart from dopaminergic dysfunction are likely to be involved in the pathogenesis of RLS.

Concomitant psychotropic medication use during treatment of schizophrenia patients: longitudinal results from the CATIE study.

OBJECTIVE: This study is a post hoc analysis of additions of antidepressants, anxiolytics, and sedative/hypnotics in treatment of patients randomized to antipsychotic treatment in the CATIE study, which recruited a chronic, "real world" schizophrenia sample and followed patients for up to eighteen months. We examined baseline predictors of initiation, time until initiation, and duration of treatment with antidepressants, anxiolytics, and sedative/hypnotics in CATIE study participants. METHODS: Psychotropic medication use by 1,449 CATIE study participants was documented at each study visit. Baseline demographic and clinical predictors of initiation, of time to initiation, and of duration of treatment of Concomitant Psychotropic Medications (CPMs) in each category (antidepressant, anxiolytic, and sedative/hypnotics) were identified through multiple regression analyses. RESULTS: Initiation of new CPMs post baseline by CATIE clinicians was moderately frequent, with 14.6% of patients receiving antidepressants, 13.7% receiving anxiolytics, and 11.2% receiving sedative/hypnotics. Predictors of antidepressant initiation (14.6% of group) were being female or white, and having a prior diagnosis of depression or symptoms of depression at baseline. Patients with higher positive symptom scores and younger patients were started on antidepressants sooner. Duration of antidepressant treatment was longer in patients with less education and in those with a history of alcohol abuse/dependence. Predictors of anxiolytic initiation (13.7% of group) were not being of African-American race, being separated/divorced, younger age, higher body mass index, and akathisia. Time to anxiolytic initiation was shorter in patients who were separated or divorced and in patients with better neurocognitive functioning. Duration of anxiolytic treatment was shorter for African Americans and longer in patients with better instrumental role functioning. Predictors of sedative/hypnotic use (11.2% of group) were depressive symptoms and prior diagnosis of an anxiety disorder. Time to initiation of sedative/hypnotics was longer for those with depressive symptoms and shorter for those with a history of alcohol abuse/dependence. CONCLUSIONS: Sedative/hypnotics, anxiolytics, and antidepressants were commonly used CPMs in schizophrenia during the CATIE trial, where patients were being seen frequently and antipsychotic treatment was optimized. Randomized, controlled clinical trials examining adjunctive use of antidepressants, anxiolytics and sedative/hypnotics to target symptoms of anxiety, depression, and insomnia in patients with schizophrenia are needed to adequately address the efficacy of these interventions.

Alternative methods for testing treatment effects on the basis of multiple outcomes: simulation and case study.

In clinical trials multiple outcomes are often used to assess treatment interventions. This paper presents an evaluation of likelihood-based methods for jointly testing treatment effects in clinical trials with multiple continuous outcomes. Specifically, we compare the power of joint tests of treatment effects obtained from joint models for the multiple outcomes with univariate tests based on modeling the outcomes separately. We also consider the power and bias of tests when data are missing, a common feature of many trials, especially in psychiatry. Our results suggest that joint tests capitalize on the correlation of multiple outcomes and are more powerful than standard univariate methods, especially when outcomes are missing completely at random. When outcomes are missing at random, test procedures based on correctly specified joint models are unbiased, while standard univariate procedures are not. Results of a simulation study are reported, and the methods are illustrated in an example from the Clinical Antipsychotic Trials of Intervention Effectiveness for schizophrenia.

Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia.

OBJECTIVE: We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. METHOD: This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. RESULTS: Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. CONCLUSIONS: Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00014001.