Nursing Staff Factors Contributing to Seclusion in Acute Mental Health Care - An Explorative Cohort Study.

BACKGROUND: Seclusion is a controversial intervention. Efficacy with regard to aggressive behaviour has not been demonstrated, and seclusion is only justified for preventing safety hazards. Previous studies indicate that nursing staff factors may be predictors for seclusion, although methodological issues may have led to equivocal results. OBJECTIVE: To perform a prospective cohort study to determine whether nursing staff characteristics are associated with seclusion of adult inpatients admitted to a closed psychiatric ward. METHOD: We studied the association between nurses' demographics and incidence of seclusion during every shift. Data were collected during five months in 2013. Multiple logistic regression was used for analysis. RESULTS: In univariable analysis, we found a non-significant association between seclusion and female gender, odds ratio (OR) = 5.27 (0.98-28.49) and a significant association between seclusion and nurses' large physical stature, OR = 0.21 (0.06-0.72). We found that physical stature is the most substantial factor, although not significant: ORadjusted = 0.27 (0.07-1.04). CONCLUSION: Nurses' gender may be a predictor for seclusion, but it seems to be mediated by the effect of physical stature. We used a rigorous, census-based, prospective design to collect data on a highly detailed level and found a large effect of physical stature of nurses on seclusion. We found nurses' physical stature to be the most substantial predictor for seclusion. These and other factors need to be explored in further research with larger sample size.

Early Nonresponse in the Antipsychotic Treatment of Acute Mania: A Criterion for Reconsidering Treatment? Results From an Individual Patient Data Meta-Analysis.

OBJECTIVE: To investigate whether early nonresponse to antipsychotic treatment of acute mania predicts treatment failure and, if so, to establish the best definition or criterion of an early nonresponse. DATA SOURCES: Short-term efficacy studies assessing antipsychotics that were submitted to the Dutch Medicines Evaluation Board during an 11-year period as part of the marketing authorization application for the indication of acute manic episode of bipolar disorder. Pharmaceutical companies provided their raw patient data, which enabled us to perform an individual patient data meta-analysis. STUDY SELECTION: All double-blind, randomized, placebo-controlled trials assessing the efficacy of antipsychotics for acute manic episode of bipolar disorder were included (10 trials). DATA EXTRACTION: All patients with data available for completer analysis (N = 1,243), symptom severity scores on the Young Mania Rating Scale (YMRS) at weeks 0, 1, and 2 and at study end point (week 3 or 4). RESULTS: The a priori chances of nonresponse and nonremission at study end point were 40.9% (95% CI, 38.2%-43.6%) and 65.3% (95% CI, 62.0%-68.6%), respectively. Early nonresponse in weeks 1 and 2, defined by cutoff scores ranging from a ≤ 10% to a ≤ 50% reduction in symptoms compared to baseline on the YMRS, significantly predicted nonresponse (≤ 0% symptom reduction) and nonremission (YMRS score higher than 8) in week 3. The predictive value of early nonresponse (PVnr_se) at week 1 for both nonresponse and nonremission at study end point declined linearly with increasing cutoff scores of early nonresponse; nonresponse: 76.0% (95% CI, 69.7%-82.3%) for a ≤ 10% response to 48.7% (95% CI, 45.5%-51.9%) for a ≤ 50% response; nonremission: 92.2% (95% CI, 88.3%-96.1%) for a ≤ 10% response to 76.8% (95% CI, 74.4%-79.5%) for a ≤ 50% response. A similar linear decline was observed for increasing cutoff scores of early nonresponse at week 2 for nonresponse, but not for nonremission at end point: nonresponse 90.3% (95% CI, 84.6%-96.0%) for a ≤ 10% response to 65.0% (95% CI, 61.4%-68.6%) for a ≤ 50% response; nonremission: 94.2% (95% CI, 89.7%-98.7%) for a ≤ 10% response and 93.2% (95% CI, 93.1%-95.1%) for a ≤ 50% response. Specific antipsychotic characteristics did not modify these findings at either time point (week 1: P = .127; week 2: P = .213). CONCLUSIONS: When patients fail to respond early (1-2 weeks) after the initiation of antipsychotic treatment for acute mania, clinicians should reconsider their treatment choice using a 2-stage strategy.

Does Insight Affect the Efficacy of Antipsychotics in Acute Mania?: An Individual Patient Data Regression Meta-Analysis.

Patients having an acute manic episode of bipolar disorder often lack insight into their condition. Because little is known about the possible effect of insight on treatment efficacy, we examined whether insight at the start of treatment affects the efficacy of antipsychotic treatment in patients with acute mania. We used individual patient data from 7 randomized, double-blind, placebo-controlled registration studies of 4 antipsychotics in patients with acute mania (N = 1904). Insight was measured with item 11 of the Young Mania Rating Scale (YMRS) at baseline and study endpoint 3 weeks later. Treatment outcome was defined by (a) mean change score, (b) response defined as 50% or more improvement on YMRS, and (c) remission defined as YMRS score less than 8 at study endpoint. We used multilevel mixed effect linear (or logistic) regression analyses of individual patient data to assess the interaction between baseline insight and treatment outcomes. At treatment initiation, 1207 (63.5%) patients had impaired or no insight into their condition. Level of insight significantly modified the efficacy of treatment by mean change score (P = 0.039), response rate (P = 0.033), and remission rate (P = 0.043), with greater improvement in patients with more impaired insight. We therefore recommend that patients experiencing acute mania should be treated immediately and not be delayed until patients regain insight.

Viral metagenomics in drug-naïve, first-onset schizophrenia patients with prominent negative symptoms.

Although several studies suggest a virus or (endogenous) retrovirus involvement at the time of onset of schizophrenia, the unequivocal identification of one or more infectious agents, by means of an undirected catch-all technique, has never been conducted. In this study VIDISCA, a virus discovery method, was used in combination with Roche-454 high-throughput sequencing as a tool to determine the possible presence of viruses (known or unknown) in blood of first-onset drugs-naïve schizophrenic patients with prominent negative symptoms. Two viruses (the Anellovirus Torque Teno virus and GB virus C) were detected. Both viruses are commonly found in healthy individuals and no clear link with disease was ever established. Viruses from the family Anelloviridae were also identified in the control population (4.8%). Besides, one patient sample was positive for human endogenous retroviruses type K (HML-2) RNA but no specific predominant strain was detected, instead 119 different variants were found. In conclusion, these findings indicate no evidence for viral or endogenous retroviral involvement in sera at the time of onset of schizophrenia.

Reduced maternal levels of common viruses during pregnancy predict offspring psychosis: potential role of enhanced maternal immune activity?

Viral infections during the prenatal or early childhood periods are one of the environmental factors which might play an etiological role in psychoses. Several studies report higher antibody levels against viruses during pregnancy in blood of mothers of offspring with psychotic disorders, but the presence of such viruses has never been demonstrated. The goal of this study was to investigate the potential association between viral infections during pregnancy and progeny with psychotic disorders and, for this purpose, we performed a nested case-control study involving pregnant mothers of offspring with schizophrenia or bipolar disorder with psychotic features (cases, N=43) and pregnant women with healthy offspring (controls, N=95). Since several potential viral candidates have been suggested in prior work, a broad-spectrum virus detection system was necessary. A metagenomic analysis performed with the virus discovery method VIDISCA-454 revealed only common blood-associated viruses in all cohorts. However, a significantly lower viral prevalence was detected in the group of cases and in the sub-population of pregnant mothers of offspring with schizophrenia (p<0.05). Consistent with the existing inverse correlation between the level of these viruses and the immunocompetence of an individual, we hypothesized the presence of a higher immune activity during pregnancy in mothers whose offspring later develop a psychotic disorder as compared to controls. Combining our results with previously available literature data on antibody levels during the gestation period suggests that a more prominent maternal immune activity can be considered a risk factor for developing psychosis.

Is deep brain stimulation a treatment option for anorexia nervosa?

Anorexia nervosa (AN) is a severe psychiatric disorder with high rates of morbidity, comorbidity and mortality, which in a subset of patients (21%) takes on a chronic course. Since an evidence based treatment for AN is scarce, it is crucial to investigate new treatment options, preferably focused on influencing the underlying neurobiological mechanisms of AN. The objective of the present paper was to review the evidence for possible neurobiological correlates of AN, and to hypothesize about potential targets for Deep brain stimulation (DBS) as a treatment for chronic, therapy-refractory AN. One avenue for exploring new treatment options based on the neurobiological correlates of AN, is the search for symptomatologic and neurobiologic parallels between AN and other compulsivity- or reward-related disorders. As in other compulsive disorders, the fronto-striatal circuitry, in particular the insula, the ventral striatum (VS) and the prefrontal, orbitofrontal, temporal, parietal and anterior cingulate cortices, are likely to be implicated in the neuropathogenesis of AN. In this paper we will review the few available cases in which DBS has been performed in patients with AN (either as primary diagnosis or as comorbid condition). Given the overlap in symptomatology and neurocircuitry between reward-related disorders such as obsessive compulsive disorder (OCD) and AN, and the established efficacy of accumbal DBS in OCD, we hypothesize that DBS of the nucleus accumbens (NAc) and other areas associated with reward, e.g. the anterior cingulated cortex (ACC), might be an effective treatment for patients with chronic, treatment refractory AN, providing not only weight restoration, but also significant and sustained improvement in AN core symptoms and associated comorbidities and complications. Possible targets for DBS in AN are the ACC, the ventral anterior limb of the capsula interna (vALIC) and the VS. We suggest conducting larger efficacy studies that also explore the functional effects of DBS in AN.

Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study.

OBJECTIVE: To estimate the incidence rates (IRs) of bipolar I and bipolar II disorders in the general population according to sociodemographic population characteristics. METHODS: A cohort study (during the years 1996-2007) was conducted in a general practitioners research database with a longitudinal electronic record of 800000 patients throughout the Netherlands [the Integrated Primary Care Information (IPCI) database]. Cases of bipolar disorder were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, degree of urbanization, and degree of deprivation. RESULTS: The overall IR of bipolar disorder was 0.70/10000 person-years (PY) [95% confidence interval (CI): 0.57-0.83]; the IR of bipolar I disorder was 0.43/10000 PY (95% CI: 0.34-0.55) and the IR of bipolar II disorder was 0.19/10000 PY (95% CI: 0.13-0.27). Two peaks in the age at onset of the disorder were noticed: one in early adulthood (15-24 years; 0.68/10000 PY) and a larger peak in later life (45-54 years; 1.2/10000 PY). In bipolar II disorder, only one peak, in the 45-54 year age category (IR 0.42/10000 PY), was found. The IRs of bipolar disorder were significantly higher in deprived areas. Similar rates were found for men compared to women and in urban compared to rural areas. No association was found between the onset of first (hypo)manic episode and month or season of birth. CONCLUSIONS: We found two peaks in the age at onset of bipolar disorder, one in early adulthood and one in later life, the former consisting mainly of bipolar I disorder subjects. The incidence of bipolar disorder is higher in deprived areas. The onset of bipolar disorder is not associated with gender, urbanization, or month or season of birth.

Annual incidence rate of schizophrenia and schizophrenia spectrum disorders in a longitudinal population-based cohort study.

BACKGROUND: Longitudinal incidence studies of schizophrenia spectrum disorders (SSD) performed in mental health service organizations are prone to confounding factors not found in research performed in the general population. OBJECTIVES: To estimate the incidence rates (IRs) over a 10-year period of SSD (broadly defined) and schizophrenia (narrowly defined) in the general population and to analyze associated risk factors. METHODS: A cohort study (1996-2006) in a large general practitioners research database was conducted with longitudinal medical records of 350,524 patients throughout the Netherlands. Cases of SSD were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, date of birth, degree of urbanicity and deprivation. RESULTS: Overall IR of SSD in this population was 22/100,000 person years (PY) (95% CI 19-24). IR of schizophrenia was 12/100,000 PY (95% CI 10-14). Period prevalence was 3.5 per 1,000 PY. IRs were higher in men compared to women, had a peak at age 15-25 years, decreasing rapidly after 25 years by 40% per 10 years. IRs of SSD were significantly higher in urban areas, irrespective of deprivation. No association was found between IRs of SSD and living in deprived areas or month of birth. There was no significant time trend of the IR during the period under study. CONCLUSIONS: IRs of SSD are higher in urban areas, independent of social deprivation. Age- and gender-specific differences in IR were found. The magnitude of these differences was larger in narrowly defined schizophrenia than in SSD.

Deep brain stimulation for obsessive-compulsive disorder is associated with cortisol changes.

Deep brain stimulation (DBS) is an effective treatment for obsessive-compulsive disorder (OCD), but its mechanism of action is largely unknown. Since DBS may induce rapid symptomatic changes and the pathophysiology of OCD has been linked to the hypothalamic-pituitary-adrenal (HPA) axis, we set out to study whether DBS affects the HPA axis in OCD patients. We compared a stimulation ON and OFF condition with a one-week interval in 16 therapy-refractory OCD patients, treated with DBS for at least one year, targeted at the nucleus accumbens (NAc). We measured changes in 24-h urinary excretion of free cortisol (UFC), adrenaline and noradrenaline and changes in obsessive-compulsive (Y-BOCS), depressive (HAM-D) and anxiety (HAM-A) symptom scores. Median UFC levels increased with 53% in the OFF condition (from 93 to 143nmol/24h, p=0.12). There were no changes in urinary adrenaline or noradrenaline excretion. The increase in Y-BOCS (39%), and HAM-D (78%) scores correlated strongly with increased UFC levels in the OFF condition. Our findings indicate that symptom changes following DBS for OCD patients are associated with changes in UFC levels.

Incidence and prevalence of "diagnosed OCD" in a primary care, treatment seeking, population.

OBJECTIVE: To obtain valid and accurate estimates of the incidence and prevalence of OCD in a treatment-seeking primary care population and to compare these estimates with estimates from epidemiological community studies. METHODS: A retrospective cohort study (1996-2007) was conducted in a GP research database with longitudinal electronic patient record data of 800,000 patients throughout The Netherlands. OCD was ascertained and classified by systematic review of computerized longitudinal medical records. Age and gender specific incidence rates were calculated per calendar year as the number of newly diagnosed cases per 100 person years. RESULTS: Among 577,085 eligible patients, 346 patients were newly diagnosed with OCD resulting in a 1-year treatment-seeking incidence of 0.016% (95% CI: 0.014-0.018). Across the entire study period, a total of 780 patients had a clinical diagnosis of OCD resulting in a treatment-seeking prevalence of 0.14% (95% CI: 0.126-0.145). The incidence rate was highest among women and between the age of 20 and 29. No significant changes over time were observed. CONCLUSIONS: The incidence rate and prevalence of OCD in treatment-seeking GP patients are at least 3 times lower than estimates known from the most conservative epidemiological community studies, suggesting that OCD may be under recognised and under treated.

Hepatic insulin resistance in antipsychotic naive schizophrenic patients: stable isotope studies of glucose metabolism.

OBJECTIVE: Our objective was to measure insulin sensitivity and body composition in antipsychotic-naive patients with DSM IV schizophrenia and/or schizoaffective disorder compared with matched controls. DESIGN: Seven antipsychotic medication-naive patients fulfilling the DSM IV A criteria for schizophrenia/schizoaffective disorder were matched for body mass index, age, and sex with seven control subjects. We measured endogenous glucose production and peripheral glucose disposal using a hyperinsulinemic euglycemic clamp (plasma insulin concentration approximately 200 pmol/liter) in combination with stable isotopes. Fat content and fat distribution were determined with a standardized single-slice computed tomography scan and whole body dual-energy x-ray absorptiometry. RESULTS: Endogenous glucose production during the clamp was 6.7 micromol/kg x min (sd 2.7) in patients vs. 4.1 micromol/kg x min (sd 1.6) in controls (P = 0.02) (95% confidence interval -5.2 to 0.006). Insulin-mediated peripheral glucose uptake was not different between patients and controls. The amount of sc abdominal fat in patients was 104.6 +/- 28.6 cm(3) and 63.7 +/- 28.0 cm(3) in controls (P = 0.04) (95% confidence interval 4.4-77.2). Intraabdominal fat and total fat mass were not significantly different. CONCLUSIONS: Antipsychotic medication-naive patients with schizophrenia or schizoaffective disorder display hepatic insulin resistance compared with matched controls. This finding cannot be attributed to differences in intraabdominal fat mass or other known factors associated with hepatic insulin resistance and suggests a direct link between schizophrenia and hepatic insulin resistance.

Magnitude of effect of lithium in short-term efficacy studies of moderate to severe manic episode.

OBJECTIVES: To provide an accurate estimation of the magnitude of effect of lithium in short-term efficacy studies conducted in patients with moderate to severe manic episode. METHODS: All placebo-controlled randomized studies submitted to the Medicines Evaluation Board (MEB) in which lithium was used as the third study arm were selected for the meta-analysis. The studies were part of registration files submitted to the MEB between the years 1997 and 2005. In addition, Medline and EMbase searches were conducted with the key words 'manic' ('mania' for the EMbase search) and 'placebo' in order to identify additional placebo-controlled studies of lithium. This search was updated until March 1, 2006. Two effect size indicators were used based on the primary outcome measure of each study: Cohen's standardized effect size based on the difference in mean change from baseline, and numbers needed to treat (NNT) based on the difference in treatment response defined as >or=50% improvement from baseline on day 21. RESULTS: Six studies were identified. They involved a combined total of 470 patients in the lithium groups and 562 in the placebo groups. The overall standardized effect size was 0.40 [95% confidence interval (CI): 0.28, 0.53] and the overall NNT for response was 6 (95% CI: 4, 13). In the placebo groups response rates varied from 21% to 47%. CONCLUSIONS: The results indicate that lithium is an effective drug in the treatment of moderate to severe manic episode. The variability in placebo response indicates that a placebo control arm in efficacy studies among patients with moderate to severe manic episode is necessary.

Antidepressants use in children and adolescents and the risk of suicide.

OBJECTIVE: Antidepressants use in paediatric patients has been linked with risk of suicidal behaviours. The aim of this paper, therefore, is to examine whether all antidepressants are associated with such risk. METHOD: All 22 paediatric short-term placebo-controlled trials of SSRIs and NSRIs that were submitted to European registration authorities by pharmaceutical companies were identified and examined for events related to suicidality, which were defined as suicide, suicide attempts or suicidal thoughts. Random effect meta-analysis was used to combine the information from all trials. RESULTS: No completed suicides were reported. However, for each compound there was at least one study with an increased risk for events related to suicidality in the active compound group. The overall OR for these events in the depression studies was 1.67 (95% CI: 1.05-2.65) and for anxiety 1.33 (95% CI: 0.33-5.35). CONCLUSIONS: Caution is called for in the use of all SSRIs and NSRIs in the paediatric population. Furthermore, in the absence of contradictory information, caution in the use of other antidepressants in this population should be exercised as well (e.g. tricyclic antidepressants).

Suicide risk in placebo-controlled trials of treatment for acute manic episode and prevention of manic-depressive episode.

OBJECTIVE: The authors' goal was to investigate whether there is a greater suicide risk in the placebo arms of placebo-controlled studies of active medication for the treatment of acute manic episode and the prevention of manic/depressive episode. If so, this would be a strong ethical argument against the conduct of such studies. METHOD: All placebo-controlled, double-blind, randomized trials of medication for the treatment of acute manic episode and the prevention of manic/depressive episode that were part of a registration dossier submitted to the regulatory authority of the Netherlands, the Medicines Evaluation Board, between 1997 and 2003, were reviewed for occurrence of suicide and attempted suicide. RESULTS: In 11 placebo-controlled studies of the treatment of acute manic episode, including 1,506 patients (117 person-years) in the combined active compound group and 1,005 patients (71 person-years) in the combined placebo group, no suicides and no suicide attempts occurred. In four placebo-controlled studies of the prevention of manic/depressive episode, including 943 patients (406 person-years) in the combined active compound group and 418 patients (136 person-years) in the combined placebo group, two suicides (493/100,000 person-years of exposure) and eight suicide attempts (1,969/100,000 person-years of exposure) occurred in the combined active compound group, but no suicides and two suicide attempts (1,467/100,000 person-years of exposure) occurred in the combined placebo group. CONCLUSIONS: Concern about greater risk of suicide or attempted suicide in the placebo group should not be an argument against the conduct of placebo-controlled trials for these indications, provided that appropriate precautions are taken.

How real are patients in placebo-controlled studies of acute manic episode?

OBJECTIVE: To determine whether the results from placebo-controlled studies conducted in patients with manic episode can be generalised to a routine population of hospitalised acute manic patients. METHODS: A list of four most prevalent inclusion and the nine most prevalent exclusion criteria was constructed for participation in previous randomised-controlled trials (RCTs). On the basis of this list, a consecutive series of 68 patients with 74 episodes of acute mania who had been referred for routine treatment were retrospectively assessed to determine their eligibility for a hypothetical but representative randomised controlled trial. RESULTS: Only 16% of the manic episodes would qualify for the hypothetical trial (male episodes 28%, female episodes 10%), whereas 37%, 20% and 27% of the manic episodes would have to be excluded because they did no fulfil one, two or at least three of the inclusion or exclusion criteria. The most common exclusion criterion was "no use of contraceptives". If this criterion was not taken into account, 28% of the male episodes and 33% of the female episodes would qualify for inclusion in the hypothetical study. Apart from the use of contraceptives, no significant differences between male and female episodes were observed in the reasons for exclusion: 11% suicidal ideation, 29% prior mood stabilising medication, 1% depot medication, 22% other axis I diagnosis, 27% internal disease somatic disease, 5% neurological disorder, 15% alcohol use disorder and 10% drug use disorder. CONCLUSION: Only a small percentage acute manic episodes in a routine mental hospital seem to qualify for a standard placebo-controlled RCT. It could be argued, however, that certain exclusion criteria (e.g. no use of contraceptives) are not very likely to reduce the external validity of a standard RCT. In contrast, some other exclusion criteria (e.g. comorbid alcohol and drug use disorders) may have resulted in an overestimation of the efficacy of anti-manic medications. These notions should be taken into account when evaluating the results of RCTs in bipolar patients with an acute manic episode.

Response to tricyclic antidepressants: independent of gender?

OBJECTIVE: The authors examined gender differences in response to tricyclic antidepressants. METHOD: A total of 30 randomized, placebo-controlled trials that included 3,886 patients (1,555 men and 2,331 women), submitted between 1979 and 1991 in order to obtain marketing authorization, were reviewed. Gender differences in response to treatment were tested in various multiple regression models using a variety of response definitions. RESULTS: Different response definitions all pointed to no gender difference in the efficacy of tricyclic antidepressants. The estimated effect size was similar for women younger and older than age 50 and for men. CONCLUSIONS: Tricyclic antidepressant response is independent of gender.

Suicide risk in placebo vs active treatment in placebo-controlled trials for schizophrenia.

BACKGROUND: If there is an increased risk of suicide in the placebo arms of placebo-controlled studies in patients with schizophrenia, it would be a strong ethical argument against the conduct of placebo-controlled studies in this patient population. We tested whether the risk of suicide and attempted suicide in the placebo arms of placebo-controlled studies among patients with schizophrenia is higher than in the active treatment arms of such studies. METHODS: All placebo-controlled double-blind studies that were part of a registration dossier for the indication schizophrenia, and that were submitted to the regulatory authority of the Netherlands from January 1, 1992, through December 31, 2002, were reviewed for suicide and attempted suicide. RESULTS: In 31 studies, 7152 patients were included: 1888 in placebo groups (398.2 person-years) and 5264 in active compound groups (981.3 person-years). One suicide occurred in the placebo groups (0.05%, or an incidence rate of 251 per 100,000 years of exposure) and 1 in the active compound groups (0.02%, or an incidence rate of 102 per 100,000 years of exposure). This difference was not statistically significant. Two attempted suicides occurred in the placebo groups (0.11%, or an incidence rate of 502 per 100,000 years of exposure) and 11 in the active compound groups (0.21%, or an incidence rate of 1121 per 100,000 years of exposure). This difference was also not statistically significant. CONCLUSION: Concern about increased risk of suicide or attempted suicide in the placebo group should not be an argument against the conduct of placebo-controlled trials in schizophrenia, provided that appropriate precautions are taken.

Amisulpride: is there a treatment for negative symptoms in schizophrenia patients?

In this article we report on a meta-analysis of the published studies of amisulpride conducted in order to demonstrate efficacy on primary negative symptoms in schizophrenia. Four placebo-controlled studies were conducted in patients with predominantly negative symptoms. In all studies a significant improvement was observed on the Scale for the Assessment of Negative Symptoms (SANS) in the amisulpride groups (50-300 mg daily) as compared to placebo. The improvement on the SANS was not accompanied by a simultaneous improvement on the Scale for the Assessment of Positive Symptoms (SAPS) or a decrease in extrapyramidal symptoms (EPS) in three of the four studies, indicating a genuine effect on primary negative symptoms. The overall analysis shows that the improvement on the SANS was accompanied by a small simultaneous improvement on the SAPS. Moreover, in the studies where depressive symptoms were measured, a significant improvement was also shown in favor of amisulpride. However, as the SAPS and the Montgomery Asberg Depression Rating Scale (MADRS) baseline scores were rather low, the improvement on both scales in favor of amisulpride is probably not responsible for the improvement on the SANS. A positive correlation was found between the severity on the mean SANS score at baseline and mean improvement at endpoint, and a surprisingly high success rate was observed in the placebo groups, indicating either that primary negative symptoms are not as persistent as had previously been thought, or that the concept of primary negative symptoms should be reconsidered. Probably amisulpride is efficacious on these nonenduring primary negative symptoms.