Jitschak G. Storosum

Short-term efficacy of tricyclic antidepressants revisited: A meta-analytic study

The original data from the placebo-arms and the tricyclic-arms of all parallel randomized controlled three-arm studies, which had been conducted in the period 1979-1991 for a drug under development in order to obtain marketing authorization for the indication major depression, were included in a meta-analysis. Thirty-two placebo-controlled studies including 4314 patients were analyzed. The intention to treat analysis resulted in 46% responders (at least 50% improvement on the Hamilton Depression Rating Scale) in the tricyclic antidepressant group and 31% in the placebo-group (CI(95%-difference) 11.5-17.1%). The number needed to treat for responders was 7 (CI(95%) 5-8). In 10 out of 32 studies, a statistically significant difference in favor of tricyclic antidepressant compared to placebo was found for responders. The responder rate in the placebo-group varied from 6 to 52%. We conclude that tricyclic antidepressants are efficacious in the short-term treatment of major depression. However, the magnitude of the effect is rather modest. Because 69% of the placebo-controlled studies with a tricyclic antidepressant did not show a statistically significant difference in favor of tricyclic antidepressant and the placebo rate varied considerably from study to study, equivalence studies with tricyclic antidepressant as comparator without a placebo-control are not sufficient for demonstrating efficacy. Therefore in major depression, placebo-controlled studies are still necessary to demonstrate efficacy.

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).

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

To estimate the incidence rates (IRs) of bipolar I and bipolar II disorders in the general population according to sociodemographic population characteristics.

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.

SCHIZOPHRENIA : DO WE REALLY NEED PLACEBO-CONTROLLED STUDIES?

OBJECTIVE To investigate whether placebo control is necessary to prove efficacy in short-term studies in schizophrenia. DESIGN This study compares the efficacy results of placebo-controlled studies versus positive controlled studies, that is controlled studies without a placebo control, in the short-term treatment of chronic schizophrenia. RESULTS Concerning mean improvement on the BPRS, the placebo arms showed in two cases a worsening, in one case almost no change, and in the remaining studies (6) the improvement was between 1 and 5%. The percentage mean improvement in the haloperidol arms of the placebo-controlled studies was comparable to the percentage mean improvement in the corresponding arms of the non-placebo-controlled studies. The highest percentage responders in the placebo-groups was 43% and the lowest was 6%. Moreover the responder rates in the atypical antipsychotic and haloperidol arms of the non-placebo-controlled studies were, in two of the three studies, in the same order of magnitude as the responder rates of the placebo arms in the placebo-controlled studies. The overall dropout rates in the placebo arms was between 48% and 80% and were higher than the drop out rates in the atypical neuroleptic arms and haloperidol arms of the placebo-controlled studies. The dropout rates due to an insufficient response in the atypical neuroleptic arms and haloperidol arms of the non-placebo-controlled studies were lower when compared to corresponding treatment arms of the placebo-controlled studies. CONCLUSION In contrast to the mean improvement on the BPRS, responder rates in the placebo arms varied considerably from study to study. Responder rates in the atypical antipsychotic and haloperidol arms of the non-placebo-controlled studies were, in two of the three studies, of the same order of magnitude as the responder rates of the placebo arms in the placebo-controlled studies. These results indicate that placebo control is necessary. Moreover as responders are a more clinically relevant outcome measure when compared to mean improvement on a rating scale, placebo-controlled studies are still needed. However, consensus on responder definition should be agreed upon. For the moment, alternatives to placebo-controlled studies are inadequate in demonstrating efficacy in studies with schizophrenic patients.

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.

Abstract 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.

Rapid effects of deep brain stimulation reactivation on symptoms and neuroendocrine parameters in obsessive-compulsive disorder.

Improvement of obsessions and compulsions by deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) is often preceded by a rapid and transient mood elevation (hypomania). In a previous study we showed that improvement of mood by DBS for OCD is associated with a decreased activity of the hypothalamus–pituitary adrenal axis. The aim of our present study was to evaluate the time course of rapid clinical changes following DBS reactivation in more detail and to assess their association with additional neuroendocrine parameters. We included therapy-refractory OCD patients treated with DBS (>1 year) and performed a baseline assessment of symptoms, as well as plasma concentrations of thyroid-stimulating hormone (TSH), prolactin, growth hormone, copeptin and homovanillic acid. This was repeated after a 1-week DBS OFF condition. Next, we assessed the rapid effects of DBS reactivation by measuring psychiatric symptom changes using visual analog scales as well as repeated neuroendocrine measures after 30 min, 2 h and 6 h. OCD, anxiety and depressive symptoms markedly increased during the 1-week OFF condition and decreased again to a similar extent already 2 h after DBS reactivation. We found lower plasma prolactin (41% decrease, P=0.003) and TSH (39% decrease, P=0.003) levels during DBS OFF, which increased significantly already 30 min after DBS reactivation. The rapid and simultaneous increase in TSH and prolactin is likely to result from stimulation of hypothalamic thyrotropin-releasing hormone (TRH), which may underlie the commonly observed transient mood elevation following DBS.

Impact of DSM-5 Changes on the Diagnosis and Acute Treatment of Schizophrenia

OBJECTIVE To examine the consequences and validity of changes in Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 diagnostic criteria for schizophrenia, eg, omission of subtypes, using a large dataset of double-blind, randomized, placebo-controlled schizophrenia trials. METHODS Data from 22 short-term efficacy registration trials of second generation antipsychotics for the treatment of acute psychotic episodes in patients with schizophrenia (N = 5233), submitted to the Dutch regulatory authority were analyzed. We examined whether patients in these pre-DSM-5 trials met the diagnostic criteria for schizophrenia according to DSM-5. Using linear regression, we examined differences in effect size between DSM-IV subtypes and between DSM-5 symptom dimensions. RESULTS Over 99.5% of the patients met DSM-5 diagnostic criteria for schizophrenia and no differences in effect size were found between schizophrenia subtypes (P = .65). Symptom dimensions that respond best to treatment with second generation antipsychotics were hallucinations, delusions, disorganized speech, and mania (Hedges g -0.23 to -0.31). CONCLUSIONS Results of clinical trials in patients with pre-DSM-5 schizophrenia also apply to patients diagnosed with DSM-5 schizophrenia. Omission of the classic subtypes is justified as they are not predictive of response to treatment. The DSM-5 C-RDPSS scale adds valuable information to the categorical diagnosis of schizophrenia, which is relevant for antipsychotic response.

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.