Diederik E. Tenback

Dyskinesia and parkinsonism in antipsychotic-naive patients with schizophrenia, first-degree relatives and healthy controls: a meta-analysis.

BACKGROUND Several studies have reported the presence of dyskinesia and parkinsonism in antipsychotic-naive patients with schizophrenia as well as in their first-degree relatives. These movement disorders may therefore form an integral part of the illness and its (genetic) liability. METHOD A systematic search was conducted in the Medline, EMBASE, and PsychINFO databases to identify studies reporting on dyskinesia and parkinsonism assessed in antipsychotic-naive patients with schizophrenia (n = 213) and controls (n = 242) and separately in nonill first-degree relatives (n = 395) and controls (n = 379). Effect sizes were pooled using random-effect models to calculate odds ratios (ORs) to compare the risk of these movement disorders among patients and healthy relatives each with matched controls. RESULTS Antipsychotic-naive schizophrenia was found to be strongly associated with dyskinesia (OR: 3.59, 95% confidence interval [CI]: 1.53-8.41) and parkinsonism (OR: 5.32, 95% CI: 1.75-16.23) compared with controls. Dyskinesia and parkinsonism were also significantly more prevalent in healthy first-degree relatives of patients with schizophrenia as compared with healthy controls (OR: 1.38, 95% CI: 1.06-1.81, and OR: 1.37, 95% CI: 1.05-1.79, respectively). CONCLUSION The results suggest that movement disorders, and by inference abnormalities in the nigrostriatal pathway, are not only associated with schizophrenia itself but may also be related to the (genetic) risk of developing the disease.

Does cannabis use affect treatment outcome in bipolar disorder? A longitudinal analysis.

Research suggests that cannabis use affects negatively on onset and outcome of schizophrenia, but less is known about possible effects in mood disorders. Bipolar in- and outpatients (N = 3459) were enrolled in an observational study. The influence of cannabis exposure on clinical and social treatment outcome measures was examined over the course of 1 year, as well as the effects on these associations of third mediating variables. Over 12 months of treatment, cannabis users exhibited less compliance and higher levels of overall illness severity, mania, and psychosis compared with nonusers. Additionally, cannabis users experienced less satisfaction with life and had a lower probability of having a relationship compared with nonusers. There was little evidence that cannabis-outcome associations were mediated by third variables. An independent impact of cannabis use on psychopathologic outcomes in patients with bipolar disorder was apparent, whereas the impact on social outcomes was modest.

Non-Therapeutic Risk Factors for Onset of Tardive Dyskinesia in Schizophrenia: A Meta-Analysis

A meta‐analysis of prospective studies with schizophrenia patients was conducted to examine whether the evidence exists for risk factors for the emergence of Tardive Dyskinesia (TD) in schizophrenia. A computer assisted Medline/PubMed and Embase search was conducted in January 2008 for the years 1985–2007. Selected were truly prospective studies of incident cases of TD in a population with at least 80% patients with schizophrenia. Measures of relative risk were collected from the individual studies, either directly or by calculating the relative risk from the cox‐ or logistic regression coefficient provided in the article. Hazard Ratios and Odds Ratios were pooled using fixed and random effect models in case of multiple studies using the same measure of risk and outcome. Only eight studies satisfied the inclusion criteria reporting on 25 different single estimate risk factors. Of 25 risk factors, six concerned replicated estimates suitable for meta‐analysis. Of these, non‐white ethnic group and early extrapyramidal symptoms qualified as risk factors for the emergence of TD in schizophrenia. The association with older age was suggestive but inconclusive. Despite many reported risk factors for TD in schizophrenia, little conclusive evidence exists to corroborate this. However, the fact that early EPS predicts onset of TD has important clinical and research implications.

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.

Incidence and persistence of tardive dyskinesia and extrapyramidal symptoms in schizophrenia.

Although it has been suggested that second-generation antipsychotics (SGA) may reduce the rate of prevalent tardive dyskinesia (TD), little is known about the incidence and outcome of TD in those exposed exclusively to SGA. The incidence and subsequent persistence of TD and extrapyramidal symptoms (EPS) was calculated in a cohort of patients with schizophrenia treated predominantly with SGA. This cohort of more than 10,000 patients with schizophrenia was seen six times over a period of two years. Dichotomous measures of EPS and TD were used to calculate the yearly incidence rates of TD and EPS as well as their subsequent cumulative persistence rate in a subset of 9104 and 6285 patients at risk for TD and EPS, respectively. Of 9104 individuals who did not present with TD at baseline, 138 developed TD, yielding a TD incidence rate of 0.74% (95% CI: 0.62, 0.87) and a subsequent cumulative persistence rate of 80%. Of 6285 individuals without EPS at baseline, 464 developed EPS yielding an incidence rate of 3.7% (95% CI: 3.4, 4.0) and a subsequent cumulative persistence rate of 82%. Incidence rates of TD and EPS may be low in the SGA era. However, once emerged, these disorders prove persistent, suggesting strong moderators effects of underlying predisposing factors.

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.

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.

Tardive dyskinesia in schizophrenia is associated with prolactin-related sexual disturbances

Tardive dyskinesia (TD) may occur in never-medicated patients with psychotic illness, indicating the existence of non-medication, possibly disease-related, causes. We tested the hypothesis that, independent of the antipsychotic-induced rise in prolactin, the incidence of TD would be associated with the incidence of prolactin-related sexual disturbances (PRSD), which would be suggestive of a common pathology involving multiple dopamine tracts. Simple, global measures of TD and PRSD (loss of libido, amenorrhea, gynaecomastia, impotence, and galactorrhea) were rated in a prospective, observational European Health Outcomes Study (SOHO). New onset of TD and new onset of PRSD at 3, 6, and 12 months was analyzed in a risk set of 4263 patients using a Cox proportional hazard model yielding adjusted hazard ratios (aHR). Incidence of TD was significantly and linearly comorbid with the incidence of PRSD in both men and women. Compared to those with no PRSD, the risk for TD was 2.0 (95% CI: 1.1, 3.7) with one PRSD, 2.4 (95% CI: 1.3, 4.5) with two PRSD, and 3.6 (95% CI: 1.1, 11.8) with three PRSD. Associations were stronger in those who only had received prolactin-sparing medications (aHR per unit PRSD increase=2.0, 95% CI: 1.2, 3.3) than in those who only had received prolactin-raising medications (aHR=1.3, 95% CI: 0.9, 1.9). In people with schizophrenia, TD and PRSD show comorbidities that are independent of antipsychotic-induced alterations in plasma prolactin. This may suggest a shared, pandopaminergic pathological mechanism associated with schizophrenia itself, rather than only a medication effect.

All-cause mortality and medication risk factors in schizophrenia: a prospective cohort study.

Background It is well established that persons with schizophrenia have high mortality rates. There is conflicting evidence that antipsychotic and perhaps other medications routinely used to treat schizophrenia contribute to mortality risk. Methods A health insurer database was used to examine schizophrenia diagnosis and mortality in 2008. Information from the period 2006–2008 was used to analyze demographics and medication prescriptions. The risk set composed of patients with schizophrenia using an antipsychotic (n = 7415) and a group of randomly chosen control subjects (n = 97,726). Results The mortality risk for having a diagnosis of schizophrenia and using an antipsychotic versus the random control group was a hazard ratio (HR) of 2.6; 95% CI, 2.0–3.2. Over the 3-year period, age, receiving a first-generation antipsychotic, and the use of a mood stabilizer were associated with a higher risk of mortality: HR, 1.06; 95% CI, 1.04–1.08; HR, 2.36; 95% CI, 1.38–4.04; and HR, 8.42; 95% CI, 3.06–24.07, respectively. Conclusion Patients with schizophrenia have higher mortality rates than normal controls. The type of antipsychotic and concomitant medication can affect mortality rates in schizophrenia.

Bone mineral density in male adolescents with autism spectrum disorders and disruptive behavior disorder with or without antipsychotic treatment

OBJECTIVE To investigate the long-term effects of antipsychotic (AP) treatment and AP-induced hyperprolactinemia on bone mineral density (BMD) and body composition in male adolescents with autism spectrum disorders (ASDs) and/or disruptive behavior disorder (DBD). DESIGN Physically healthy 10- to 20-year-old boys with ASD and/or DBD, chronically treated (n=56; mean 52 months, range 16-126 months) or not treated (n=47) with an AP, were recruited to this observational study. Prolactin levels and biochemical bone parameters were measured and BMD of the lumbar spine and total body, and body composition were assessed by dual-energy X-ray absorptiometry, and volumetric BMD of the lumbar spine calculated. Group differences were tested with Students t-test, χ(2) test, Fisher exact test, and logistic regression analysis. RESULTS Forty-nine percent of the boys treated with an AP had hyperprolactinemia. The mean volumetric lumbar spine BMD z-score was lower (P=0.043), the total percentage of body fat z-score was higher (P=0.042), and biochemical bone marker carboxyterminal cross-linking telopeptide of bone collagen was lower in the AP-treated boys with hyperprolactinemia than in the AP-treated boys without hyperprolactinemia. Seven to 11% of the hyperprolactinemic boys had low BMD. The mean lumbar spine and total body BMD z-scores and body composition were similar in the boys who were or were not treated with an AP. The total study population had a lower mean lean tissue mass (mean z-score -0.37, P=0.004) and a higher percentage of total body fat (mean z-score 1.16, P<0.001) than healthy controls (normative data); biochemical bone parameters were within normal limits. CONCLUSION AP-induced hyperprolactinemia in boys with ASD or DBD may have a negative effect on lumbar spine BMD. Longitudinal studies are needed to confirm this finding and further disentangle the effects of the disorder, lifestyle, treatment, and hyperprolactinemia.