Peter N. van Harten

The five-factor model of the Positive and Negative Syndrome Scale I: confirmatory factor analysis fails to confirm 25 published five-factor solutions

OBJECTIVE The aim of this study was to test the goodness-of-fit of all previously published five-factor models of the Positive and Negative Syndrome Scale (PANSS). METHODS We used confirmatory factor analysis (CFA) with a large data set (N = 5769). RESULTS The different subsamples were tested for heterogeneity and were found to be homogeneous. This indicates that despite variability in age, sex, duration of illness, admission status, etc., in the different subsamples, the structure of symptoms is the same for all patients with schizophrenia. Although previous research has shown that a five-factor model fits the data better than models with three or four factors, no satisfactory fit for any of the 25 published five-factor models was found with CFA. CONCLUSIONS Variability in age, sex, admission status and duration of illness has no substantial effect on the structure of symptoms in schizophrenia. The lack of fit can be caused by ill-defined items that aim to measure several properties in a single rating. Another explanation is that well-defined symptoms can have two or more causes. Then a double or triple loading item should not be discarded, but included because the complexity of symptoms in schizophrenia is represented by these multiple loadings. Such a complex model not only needs confirmation by CFA, but also has to be proven stable. A 10-fold cross-validation is suggested to develop a complex and stable model.

Antipsychotic-induced tardive dyskinesia and the Ser9Gly polymorphism in the DRD3 gene: A meta analysis

BACKGROUND A polymorphic site in the gene encoding the dopamine 3 receptor (DRD3) resulting in a serine (Ser) into glycine (Gly) substitution has been shown to affect dopamine binding affinity, and may contribute to individual differences in susceptibility to antipsychotic-induced tardive dyskinesia (TD). METHODS A Medline, EMBASE and PsychINFO search of literature published between 1976 and March 2005 yielded 11 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. RESULTS The Gly allele increased the risk relative to the Ser allele (OR=1.17; 95% CI: 1.01-1.37) with evidence of publication bias. No significant genotype effects were apparent. CONCLUSIONS TD may be associated with functional variation in the DRD3 allele. However, caution is required in interpreting this finding, as there is evidence of publication bias, genetic methodology has shortcomings, and the relation between antipsychotics, schizophrenia and TD is complex.

Antipsychotic medication in children and adolescents: a descriptive review of the effects on prolactin level and associated side effects.

OBJECTIVE This review reports the incidence of hyperprolactinemia, its relationship with genotype, and prolactin-related side effects in children and adolescents treated with antipsychotics. METHOD Data on prolactin levels were available for haloperidol, pimozide, risperidone, olanzapine, clozapine, ziprasidone, and quetiapine. Twenty-nine studies were selected after a literature search in the English Medline/Embase/Psychinfo/EBM databases (1965 to August, 2008). RESULTS All antipsychotics, except clozapine, ziprasidone, and quetiapine, increase the mean prolactin level from baseline values of 8.0 ng/mL to 25-28 ng/mL after 4 weeks of treatment (reference range 0-15 ng/mL). The most and best data are available for risperidone. Five risperidone studies (n = 577) show an increase of prolactin level from 7.8 ng/mL to 17.7 ng/mL after 1 year of treatment, and two risperidone studies (n = 60) show an increase from 7.4 ng/mL to 24.9 ng/mL after 2 years of treatment. Aggregated over all antipsychotics, prolactin-related side effects, such as gynecomastia, galactorrhea, irregular menses, and sexual dysfunction, were reported by 4.8% of the children and adolescents. No data are available on bone mineral density in relation to antipsychotic-induced hyperprolactinemia in children and adolescents. Prolactin levels may be influenced by the genetic differences that influence prolactin metabolism and D2 dopamine receptor density. CONCLUSION Persistent elevation of prolactin for periods up to 2 years has been documented in maintenance treatment with risperidone. Very limited long-term data of pimozide, olanzapine, and quetiapine prohibit drawing conclusions for these antipsychotics. Systematic long-term observational studies, including specific questionnaires as well as physical examination, are needed to investigate prolactin-related side effects of antipsychotic treatment in children and adolescents.

Efficacy and safety of deep brain stimulation in patients with medication-induced tardive dyskinesia and/or dystonia: a systematic review.

BACKGROUND Tardive dyskinesia and dystonia (TDD) are severe side effects of dopamine-blocking agents, particularly antipsychotics. While deep brain stimulation (DBS) has proven effective in the treatment of TDD, little is known about the possible psychiatric complications of DBS in psychiatric patients. OBJECTIVE To assess the efficacy and safety, specifically the psychiatric side effects, of DBS in patients with medication-induced TDD. DATA SOURCES PubMed and EMBASE databases were searched systematically on May 25, 2011, for articles written in English, using the search terms deep brain stimulation AND tardive. STUDY SELECTION Of the 88 original articles retrieved, 17 studies involving 50 patients with TDD who underwent DBS were included in the review. DATA EXTRACTION Data on the severity of the movement disorders before and after DBS, as rated on the Burke-Fahn-Marsden Dystonia Rating Scale or similar scales, were extracted. Data on psychiatric symptoms before and after DBS were used to calculate the percent improvement per patient per rating scale. Overall improvement and confidence intervals were calculated using a 1-sample, 2-sided Student t test. RESULTS The mean improvement of TDD of the combined patients 3 to 76 months after implantation was 77.5% (95% CI, 71.4%-83.3%; P < .000) on the Burke-Fahn-Marsden Dystonia Rating Scale. Of the 50 patients, 1 experienced an exacerbation of depression, and 1 experienced an exacerbation of psychosis. CONCLUSIONS DBS seems to be effective and relatively safe for patients with treatment-resistant TDD; however, the results should be interpreted with caution, as most of the data are from case reports and small trials.

Use of clozapine in tardive dystonia

1. This open clinical trial (N = 7) measured the course of severe tardive dystonia in chronic psychiatric patients after discontinuation of neuroleptics and subsequent use of clozapine. 2. The dystonia was regularly assessed using the Fahn-Marsden Rating Scale. The eventual concomitant tardive dyskinesia was assessed using the Abnormal Involuntary Movement Scale. The mean follow up was 103 weeks. 3. The results for the tardive dystonia: four patients recovered totally, two improved considerably and one did not recover. 4. The results for the concomitant tardive dyskinesia: five of the seven patients had also dyskinesia, one patient had a total, two a partly remission, one had a very fluctuating course, and one patient worsened. Another patient developed dyskinesia. 5. It is suggested to consider clozapine for patients with tardive dystonia who have to continue antipsychotic treatment.

Risk of Hyperprolactinemia and Sexual Side Effects in Males 10-20 Years Old Diagnosed with Autism Spectrum Disorders or Disruptive Behavior Disorder and Treated with Risperidone

OBJECTIVE The aim of this study was to investigate the long-term treatment effects of risperidone on prolactin levels and prolactin-related side effects in pubertal boys with autism spectrum disorders (ASD) and disruptive behavior disorders (DBD). METHOD Physical healthy 10-20-year-old males with ASD (n=89) and/ or DBD (n=9) chronically treated (mean 52 months, range 16-126 months) with risperidone (group 1, n=51) or not treated with any antipsychotic (group 2, n=47) were recruited to this observational study from the child psychiatry outpatient clinic. Morning non-fasting serum prolactin levels were measured and prolactin-related side effects were assessed by means of questionnaires and physical examination. Group differences were tested with Students t, χ(2), Fisher exact, and Mann-Whitney tests, and logistic regression analysis, according to the type and distribution of data. RESULTS Hyperprolactinemia was present in 47% of subjects in group 1 but only in 2% of subjects in group 2 (odds ratio 71.9; 95% CI, 7.7; 676.3). Forty-six percent of subjects in group 1 had asymptomatic hyperprolactinemia. Current risperidone dose and 9-OH risperidone plasma level were significant predictors of hyperprolactinemia (p=0.035 and p=0.03, respectively). Gynecomastia and sexual dysfunction were present in 43% and 14% of the subjects in group 1, respectively, compared with 21% and 0% of subjects in group 2 (p=0.05 and p=0.01). Gynecomastia was not significantly associated with hyperprolactinemia. CONCLUSIONS Hyperprolactinemia is a common side effect in young males treated over the long term with risperidone. Young males treated with risperidone are more likely to report diminished sexual functioning than are those not treated with antipsychotics.

Long-Stay Psychiatric Patients: A Prospective Study Revealing Persistent Antipsychotic-Induced Movement Disorder

Objective The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness. Method Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. Results The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder. Conclusions Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.

Movement disorders in nonpsychotic siblings of patients with nonaffective psychosis

Movement disorders such as dyskinesia and Parkinsonism have frequently been reported in (drug-naïve) patients with nonaffective psychosis. Therefore movement disorders may be related to schizophrenia. Siblings of patients with nonaffective psychosis also appear to have subtle forms of movement disorders. This suggests that motor abnormalities may also be related to the risk of developing the disease. Subtle forms are not always detected with the use of the standard observation-based clinical rating scales, which are less sensitive than mechanical instrument measurement. This study compared the presence and severity of dyskinesia and Parkinsonism in 42 non-psychotic siblings of patients with nonaffective psychosis and in 38 controls as measured by mechanical instruments and clinical rating scales. There were no significant differences in movement disorders between siblings and controls on the basis of clinical assessments. However, mechanical measurements indicated that siblings compared to controls displayed significantly more dyskinesia and Parkinsonism signs. These results suggest that motor signs could be markers of vulnerability for psychosis or schizophrenia. In addition this study shows that mechanical instrument measurement of movement disorders is more sensitive than assessment with clinical rating scales. Therefore, it may be used in screening programs for populations at risk for psychosis.

The inter-relationships of tardive dyskinesia, parkinsonism, akathisia and tardive dystonia : the Curaçao Extrapyramidal Syndromes Study II

A study of the four extrapyramidal syndromes (EPS), tardive dyskinesia, parkinsonism, akathisia and tardive dystonia, was performed in the Netherlands Antilles, a well-defined catchment area with only one psychiatric hospital. The population under study (N = 194; mean age 53.1) was mainly Afro-Caribbean, and most patients were chronic. The severity of each EPS was measured with valid and reliable rating scales. The purpose was to study both the strength of the inter-relationships of EPS and the prevalence of combinations of EPS. The inter-relationships between the EPS were analyzed by means of logistic regression. The adjusted odds ratios between the various EPS revealed strong connections between the hyperkinetic syndromes (tardive dyskinesia, tardive dystonia and akathisia). Parkinsonism was found to be inversely related to tardive dyskinesia and to tardive dystonia. Almost 30% of the patients suffered from two or more EPS. The highest prevalence rates of combinations were: tardive dyskinesia combined with parkinsonism 12.9%, tardive dyskinesia combined with tardive dystonia 9.8%, and tardive dyskinesia combined with akathisia 5.2%. Our findings show a strong positive correlation between hyperkinetic forms of EPS. Furthermore, chronic psychiatric inpatients regularly suffer from combinations of EPS. Different treatment strategies are suggested for various combinations of EPS.

TARDIVE DYSKINESIA: CLINICAL PRESENTATION AND TREATMENT

Tardive dyskinesia (TD) is a common and potentially irreversible side effect of dopamine blocking agents, most often antipsychotics. It is often socially and sometimes also physically disabling. The clinical picture can be divided into orofacial, limb-truncal, and respiratory dyskinesia. The clinical options to prevent or mitigate TD include psychoeducation, systematic screening, and evaluation of the need for antipsychotics and/or dosages, managementof known risk factors, and switching to an antipsychotic with a lower risk of TD. There is no evidence-based approach for treating existing TD but several clinical interventions can be effective including discontinuing the antipsychotics or reducing the dosage, switching to clozapine, adding an antidyskinetic agent, or applying deep brain stimulation.