Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study.

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

Clinical Characteristics of Patients With Schizophrenia Who Successfully Discontinued Antipsychotics: A Literature Review.

PURPOSE/BACKGROUND: Although discontinuing antipsychotics clearly increases the risk of relapse in schizophrenia, some patients remain clinically well without continuous antipsychotic treatment. However, data on the characteristics of such patients are still scarce. METHODS/PROCEDURES: A systematic literature review was conducted to identify predictive factors for successful antipsychotic discontinuation in schizophrenia using PubMed (last search; June 2018) with the following search terms: (antipsychotic* or neuroleptic) AND (withdraw* or cessat* or terminat* or discontinu*) AND (schizophreni* or psychosis). The search was filtered with humans and English. Factors associated with a lower risk of relapse, when replicated in 2 or more studies with a follow-up period of 3 months or longer, were considered successful. FINDINGS/RESULTS: Systematic literature search identified 37 relevant articles. Mean relapse rate after antipsychotic discontinuation was 38.3% (95% confidence interval = 16.0%-60.6%) per year. Factors associated with a lower risk of relapse were being maintained on a lower antipsychotic dose before discontinuation, older age, shorter duration of untreated psychosis, older age at the onset of illness, a lower severity of positive symptoms at baseline, better social functioning, and a lower number of previous relapses. IMPLICATIONS/CONCLUSIONS: Although this literature review suggests some predictors for successful antipsychotic withdrawal in patients with schizophrenia, the very limited evidence base and unequivocally high relapse rates after discontinuation must remain a matter of serious debate for risk/benefit considerations.

Quality of life in schizophrenia and bipolar disorder: The impact of symptomatic remission and resilience.

BACKGROUND: Health-related quality of life (HRQOL) is significantly affected in individuals with schizophrenia or bipolar I disorder (BD-I). The current study investigated whether symptomatic remission and resilience might differently impact HRQOL in these patients. METHODS: Fifty-two patients with schizophrenia and 60 patients suffering from BD-I from outpatient mental health services as well as 77 healthy control subjects from the general community were included into a cross-sectional study. HRQOL and resilience were assessed using the WHOQOL-BREF and the Resilience Scale. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale or the Montgomery Asberg Depression Rating Scale and the Young Mania Rating Scale, respectively. RESULTS: Notably, both patient groups showed lower HRQOL and resilience compared to control subjects, non-remitted patients indicated lower HRQOL than remitted ones. The effect of remission on HRQOL was significantly larger in patients with BD-I than in those with schizophrenia but did not explain the difference in HRQOL between groups. Resilience predicted HRQOL in all three groups. When accounting for the effect of resilience among remitted patients, only the difference in HRQOL between schizophrenia patients and control subjects was significant. CONCLUSION: These findings demonstrate the impact of symptomatic remission and resilience on HRQOL of both patients suffering from schizophrenia and BD-I and indicate that these factors are especially relevant for HRQOL of patients with BD-I.

The Use of Long-Acting Injectable Antipsychotics in Schizophrenia.

Schizophrenia is a mostly chronic mental disorder, and symptomatic relapse is frequently observed. It is often associated with social and/or occupational decline that can be difficult to reverse. Most patients with the illness need long-term pharmacological treatment, and antipsychotic drugs represent the mainstay of clinical care. Long-acting injectable antipsychotics (LAIs) are an important alternative to oral medication, particularly advantageous in the context of compliance management. Several new-generation antipsychotics (NGAs), including risperidone, olanzapine, paliperidone, and aripiprazole, have become available as long-acting formulations, and new evidence has been accumulating. To date, all of the NGA LAIs have demonstrated a statistically and clinically significant decrease of relapse rates over placebo. The results of clinical trials comparing NGA LAIs with oral antipsychotics (OAPs) are not consistent, as being influenced considerably by study design. Superiority of LAIs to OAPs in efficacy is most evident in mirror image and cohort studies. New-generation LAIs are comparable to their oral mother compounds regarding safety and tolerability if one disregards potential injection site complications. There is little evidence of efficacy differences between the available LAIs, but they have different characteristics in terms of pharmacodynamic and pharmacokinetic profiles, injection interval, cost, requirements for oral supplementation, as well as adverse events. Considering these differences is useful for selecting LAIs for the treatment of individual patients. There is increasing evidence suggesting the use of LAIs in special patient groups, such as first-episode or forensic schizophrenia patients. This article reviews data on the use of NGA LAIs in schizophrenia and discusses current issues from clinical and methodological perspectives.

Markers of bone resorption and formation during abstinence in male alcoholic patients.

BACKGROUND: Reduced bone mineral density (BMD) is commonly found in alcohol-dependent patients. Many risk factors have been reported, yet the course of markers of bone formation and resorption in abstinent alcoholic patients have not received much attention. METHODS: In a prospective longitudinal study, we investigated BMD in male abstinent inpatients of an alcohol rehabilitation clinic aged 21 to 50 years at baseline and after 8 weeks of treatment. At baseline and at week 8, all patients had blood drawn for the analysis of liver function tests, calcium, phosphate, parathormone, 25-hydroxyvitamin D, osteocalcin (OC), serum crosslaps, sex hormones, and prolactin. BMD was determined by dual X-ray absorptiometry in the lumbar spine and the proximal right femur. We also determined the amount of physical activity prior to inpatient treatment by using the International Physical Activity Questionnaire (IPAQ). RESULTS: Low BMD was found in 15.1% of the patients for the lumbar spine, in 5.7% for the femoral neck, and in 1.9% for the total hip. BMD differed significantly from normal values, in the lumbar spine and in the femoral neck. At baseline, crosslaps were elevated in 34% of the patients, while OC levels were lowered in 17%. Over the course of the 8 weeks, we found a significant increase in OC plasma levels, indicating a higher rate of bone formation during continuous abstinence. There were also positive correlations between IPAQ scores and BMD as reflected by Z-scores in all regions, pointing to a protective effect of physical activity. CONCLUSIONS: In summary, this report confirms earlier cross-sectional studies of lowered BMD in alcoholic noncirrhotic men. We could also demonstrate that the initial imbalance between bone formation and resorption seems to adjust toward a balance between the two during abstinence.

Treatment of depression in first episode of schizophrenia: results from EUFEST.

Depressive symptomatology is an important target of treatment in first episode schizophrenia. This reanalysis of the European First Episode Schizophrenia Trial (EUFEST) describes the depressive symptomatology and the effect of antipsychotic treatment in patients suffering from first episode schizophrenia and schizophreniform disorder randomized to treatment with low dose haloperidol (n=103), amisulpride (n=104), olanzapine (n=105), quetiapine (n=104) or ziprasidone (n=82) for one year. At baseline, the mean score on the Calgary Depression Scale for Schizophrenia (CDSS) was 5.1 (±4.9) with 38.3% of patients having a CDSS score≥6, i.e. clinically relevant depressive symptom severity. During treatment depression scores decreased, the mean CDSS score being 1.1 (±2.1) and 3.0% of patients having a CDSS≥6 at 52 weeks. The proportion of patients using antidepressants during the complete trial was 18.5% in the haloperidol group, 28.6% in the olanzapine group compared to 5.8% in the quetiapine group, 12.5% in the amisulpride group, and 9.8% in the ziprasidone group. There were no differences over time in the probability of being depressed (CDSS≥6) between the 5 treatment groups after adjustment for antidepressant use, nor in a sub analysis of patients who did not take any antidepressant. Depression scores at baseline or during the trial had no effect on treatment discontinuation or on the reduction of positive symptoms. In summary, the results of EUFEST did not demonstrate a differential effect of the antipsychotics studied on depressive symptomatology in patients with first episode schizophrenia.

Facial emotion recognition and its relationship to symptomatic, subjective, and functional outcomes in outpatients with chronic schizophrenia.

Outcome in schizophrenia is multidimensional and consists of clinical and psychosocial domains. Difficulties in affect recognition are a hallmark of schizophrenia, but there is little research investigating the consequences of this deficit on patients' psychosocial status. This cross-sectional study examined the relationship of facial affect recognition and treatment outcomes in terms of psychopathology, quality of life (QOL), and psychosocial functioning. We investigated 40 regular attendees of a specialized schizophrenia outpatient clinic who had been stable both from a symptomatic and a medication perspective for a minimum of 6 months and 40 healthy volunteers who were chosen to match patients in age, sex, and education. Affect recognition was positively associated with patients' level of education and negatively with increasing age. Deficits in this area corresponded to the severity of negative and affective symptoms as well as to poor work and global functioning. These findings suggest that affect recognition is an important aspect of psychosocial functioning in stable outpatients with schizophrenia.

Sex differences in brain activation patterns during processing of positively and negatively valenced emotional words.

BACKGROUND: Previous studies have suggested that men and women process emotional stimuli differently. In this study, we used event-related functional magnetic resonance imaging (fMRI) to investigate gender differences in regional cerebral activity during the perception of positive or negative emotions. METHOD: The experiment comprised two emotional conditions (positively/negatively valenced words) during which fMRI data were acquired. RESULTS: Thirty-eight healthy volunteers (19 males, 19 females) were investigated. A direct comparison of brain activation between men and women revealed differential activation in the right putamen, the right superior temporal gyrus, and the left supramarginal gyrus during processing of positively valenced words versus non-words for women versus men. By contrast, during processing of negatively valenced words versus non-words, relatively greater activation was seen in the left perirhinal cortex and hippocampus for women versus men, and in the right supramarginal gyrus for men versus women. CONCLUSIONS: Our findings suggest gender-related neural responses to emotional stimuli and could contribute to the understanding of mechanisms underlying the gender disparity of neuropsychiatric diseases such as mood disorders.

Alterations of glucose metabolism during treatment with clozapine or amisulpride: results from a prospective 16-week study.

Although second-generation antipsychotics have notable benefits as compared to typical antipsychotics, their use has been associated with metabolic disturbances, such as alterations of glucose homeostasis. It is still being debated whether this is a class effect of second-generation antipsychotics. We conducted a prospective, open study comparing body weight, parameters of insulin resistance in schizophrenia patients treated with either clozapine (n = 10) or amisuLpride ( n = 12). All parameters were assessed monthly over a period of 12 to 16 weeks. Body mass index (BMI), fasting serum insulin levels and the Homeostasis Model Assessment (HOMA) index for insulin resistance increased significantly in patients treated with clozapine. None of these parameters increased significantly in patients treated with amisulpride. This study indicates that treatment with clozapine appears to have a higher risk to lead to metabolic disturbances than amisupride.

The neural regions sustaining episodic encoding and recognition of objects.

In this functional MRI experiment, encoding of objects was associated with activation in left ventrolateral prefrontal/insular and right dorsolateral prefrontal and fusiform regions as well as in the left putamen. By contrast, correct recognition of previously learned objects (R judgments) produced activation in left superior frontal, bilateral inferior frontal, and right cerebellar regions, whereas correct rejection of distractor objects (N judgments) was associated with activation in bilateral prefrontal and anterior cingulate cortices, in right parietal and cerebellar regions, in the left putamen, and in the right caudate nucleus. The R minus N comparison showed activation in the left lateral prefrontal cortex and in bilateral cingulate cortices and precunei, while the N minus R comparison did not reveal any positive signal change. These results support the view that similar regions of the frontal lobe are involved in episodic encoding and retrieval processes, and that the successful episodic retrieval of newly learned objects is mainly based on a frontoparietal network.

[Antipsychotic drug-induced changes in metabolism]. / Metabolische Nebenwirkungen von Antipsychotika der neuen Generation.

Antipsychotic medications are a mainstay in the treatment of schizophrenia and are widely used in other psychiatric conditions. New generation antipsychotic agents (NGAs) are increasingly replacing first generation antipsychotic agents (FGAs), mainly due to a decreased risk for extrapyramidal symptoms, better overall tolerability, as well as some efficacy advantages. However, some of these NGAs are associated with adverse metabolic effects such as substantial weight gain, the induction of insulin resistance and lipid disorders. Among these substances, clozapine and olanzapine induce the most significant weight gain, olanzapine mainly by increasing body fat and both of these antipsychotics have been associated with disturbances in glucose metabolism. Diabetes mellitus induced by treatment with some NGAs occurred in many cases within days to weeks after initiation of SGA therapy, in some cases hyperglycemia promptly resolved after discontinuation of the medication and several reports have documented recurrent hyperglycemia after a rechallenge with the same drug. One possible pathomechanism for hyperglycemia induced by these NGAs is the induction of insulin resistance via humoral and/or cellular pathways. Alternatively, NGA induced diabetes may occur because of weight gain or a change in body fat distribution with a shift to a predominantly visceral fat type or through a direct effect on insulin sensitive target tissues. In this article we like to review the metabolic side effects of NGA treatment, highlight recent advances in the pathogenesis of these metabolic complications and discuss potential treatments of these side effects.