Immune Dysfunction in Schizophrenia Spectrum Disorders.

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis.

BACKGROUND: Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs). METHODS: PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes. RESULTS: Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect. CONCLUSIONS: Some, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.

High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls.

BACKGROUND: Schizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia. METHOD: This cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance. RESULTS: BD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (ß = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (ß = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels. CONCLUSIONS: Although BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients.

Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset.

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95-1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86-0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71-0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82-0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.

Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia.

Molecular abnormalities in metabolic, hormonal and immune pathways are present in peripheral body fluids of a significant subgroup of schizophrenia patients. The authors have tested whether such disturbances also occur in psychiatrically ill and unaffected siblings of schizophrenia patients with the aim of identifying potential contributing factors to disease vulnerability. The subjects were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study. The authors used multiplexed immunoassays to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls. Consistent with the findings of previous studies, serum from schizophrenia patients contained higher levels of insulin, C-peptide and proinsulin, decreased levels of growth hormone and altered concentrations of molecules involved in inflammation. In addition, significant differences were found in the levels of some of these proteins in siblings diagnosed with mood disorders (n=16) and in unaffected siblings (n=117). Most significantly, the insulin/growth hormone ratio was higher across all groups compared with the controls. Taken together, these findings suggest the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia.

Insight change in psychosis: relationship with neurocognition, social cognition, clinical symptoms and phase of illness.

OBJECTIVE: Impaired insight is an important and prevalent symptom of psychosis. It remains unclear whether cognitive disturbances hamper improvements in insight. We investigated the neurocognitive, social cognitive, and clinical correlates of changes in insight. METHOD: One hundred and fifty-four patients with a psychotic disorder were assessed at baseline (T0 ) and after three years (T3 ) with the Birchwood Insight Scale, the Positive And Negative Syndrome Scale, measures of neurocognition and social cognition. Linear regression analyses were conducted to examine to what extend neurocognition, social cognition, clinical symptoms and phase of illness could uniquely predict insight change. Subsequently, changes in these factors were related to insight change. RESULTS: Better neurocognitive performance and fewer clinical symptoms at baseline explained insight improvements. The additional effect of clinical symptoms over and above the contribution of neurocognition was significant. Together, these factors explained 10% of the variance. Social cognition and phase of illness could not predict insight change. Changes in clinical symptoms, but not changes in neurocognitive performance were associated with insight change. CONCLUSION: Neurocognitive abilities may predict, in part, the development of insight in psychosis.

Depressive symptoms are associated with (sub)clinical psychotic symptoms in patients with non-affective psychotic disorder, siblings and healthy controls.

BACKGROUND: Depression is a clinically relevant dimension, associated with both positive and negative symptoms, in patients with schizophrenia. However, in siblings it is unknown whether depression is associated with subclinical positive and negative symptoms. Method Depressive symptoms and their association with positive and negative symptoms were examined in 813 healthy siblings of patients with a non-affective psychotic disorder, 822 patients and 527 healthy controls. Depressive episodes meeting DSM-IV-TR criteria (lifetime) and depressed mood (lifetime) were assessed with the Comprehensive Assessment of Symptoms and History (CASH) in all three groups. In the patient group, the severity of positive and negative psychosis symptoms was assessed with the CASH. In the siblings and healthy controls, the severity of subclinical psychosis symptoms was assessed with the Community Assessment of Psychic Experiences (CAPE). RESULTS: Patients reported more lifetime depressed mood and more depressive episodes than both siblings and controls. Siblings had a higher chance of meeting lifetime depressive episodes than the controls; no significant differences in depressed mood were found between siblings and controls. In all three groups the number and duration of depressive symptoms were associated with (sub)clinical negative symptoms. In the patients and siblings the number of depressive symptoms was furthermore associated with (sub)clinical positive symptoms. Finally, lifetime depressed mood showed familial clustering but this clustering was absent for lifetime depressive episodes. CONCLUSIONS: These findings suggest that a co-occurring genetic vulnerability for both depressive and psychotic symptomatology exists on a clinical and a subclinical level.

[Psychotic disorders: the need for staging]. / Stagering van psychotische stoornissen.

BACKGROUND: In psychotic disorders it is the stage of development of the disease which mainly determines the prognosis and the effectiveness of treatment. AIM: To describe and to refine the current staging and profiling of psychotic disorders and to propose a way in which to describe the course of dimensions of psychoses. METHOD: We searched the literature for articles relating to the staging of psychotic disorders. RESULTS: McGorry e.a. developed a simple classification into stages which is currently applicable to research and clinical practice. We propose a further refinement in the form of a graph from which one can see in a glance the history of clinically relevant variation. CONCLUSION: Research into the prodromal stages of diseases is needed in order to elucidate the pathophysiological mechanisms that the stages have in common and to reveal the pathways of differential development.

Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender.

BACKGROUND: Cannabis use is associated with an earlier age at onset of psychotic illness. The aim of the present study was to examine whether this association is confounded by gender or other substance use in a large cohort of patients with a non-affective psychotic disorder. METHOD: In 785 patients with a non-affective psychotic disorder, regression analysis was used to investigate the independent effects of gender, cannabis use and other drug use on age at onset of first psychosis. RESULTS: Age at onset was 1.8 years earlier in cannabis users compared to non-users, controlling for gender and other possible confounders. Use of other drugs did not have an additional effect on age at onset when cannabis use was taken into account. In 63.5% of cannabis-using patients, age at most intense cannabis use preceded the age at onset of first psychosis. In males, the mean age at onset was 1.3 years lower than in females, controlling for cannabis use and other confounders. CONCLUSIONS: Cannabis use and gender are independently associated with an earlier onset of psychotic illness. Our findings also suggest that cannabis use may precipitate psychosis. More research is needed to clarify the neurobiological factors that make people vulnerable to this precipitating effect of cannabis.

Cannabis and cognitive performance in psychosis: a cross-sectional study in patients with non-affective psychotic illness and their unaffected siblings.

BACKGROUND: The relationship between cannabis use and cognitive functioning in patients with psychosis has yielded contradictory findings. In individuals at genetic high risk for psychosis, information is sparse. The aim of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in patients with psychosis and their unaffected siblings. METHOD: We conducted a cross-sectional study in 956 patients with non-affective psychosis, 953 unaffected siblings, and 554 control subjects. Participants completed a cognitive test battery including assessments of verbal learning, set shifting, sustained attention, processing speed, working memory, acquired knowledge, reasoning and problem solving and social cognition. Cannabis use was assessed by urinalysis and by the Composite International Diagnostic Interview. Using random-effect regression models the main effects of cannabis (recency and frequency) and the interaction with status (patient, sibling, control) on cognitive functioning were assessed. RESULTS: Current cannabis use was associated with poorer performance on immediate verbal learning, processing speed and working memory (Cohen's d -0.20 to -0.33, p<0.005). Lifetime cannabis use was associated with better performance on acquired knowledge, facial affect recognition and face identity recognition (Cohen's d+0.17 to +0.33, p<0.005). There was no significant interaction between cannabis and status on cognitive functioning. CONCLUSIONS: Lifetime cannabis-using individuals might constitute a subgroup with a higher cognitive potential. The residual effects of cannabis may impair short-term memory and processing speed.

Identification of a biological signature for schizophrenia in serum.

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ~50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.

Cardiovascular variability during treatment with haloperidol, olanzapine or risperidone in recent-onset schizophrenia.

This study aimed to investigate the effects of treatment with haloperidol, olanzapine and risperidone on cardiovascular variability in patients with recent-onset schizophrenia by means of spectral analysis. Unmedicated patients (n = 18) had a higher mean heart rate and a tendency for a lower high-frequency power of heart rate variability than healthy control subjects (n = 57), indicating a decreased cardiac vagal control in unmedicated patients with schizophrenia. Patients treated with haloperidol (n = 10) showed significantly lower low-frequency power of heart rate and systolic blood pressure variability compared with olanzapine-treated patients, suggesting that haloperidol attenuated sympathetic functioning. On the contrary, olanzapine-treated patients (n = 10) showed the highest power in the low-frequency range of heart rate and systolic blood pressure variability, suggesting an increased sympathetic cardiac functioning. No significant effects of risperidone (n = 13) were found. None of the antipsychotic agents differed in their parasympathetic cardiovascular effects. We conclude that young, unmedicated patients with schizophrenia differed from controls in their parasympathetic functioning, but the antipsychotic agents haloperidol, risperidone and olanzapine induced only minor cardiovascular side effects.

[Adolescence, schizophrenia and drug abuse: interactive vulnerability. A hypothesis]. / Adolescentie, schizofrenie en drugs: interacterende kwetsbaarheid. Een hypothese.

BACKGROUND: Many studies have reported an interactive vulnerability between adolescence, schizophrenia and drug abuse. aim To discuss neurobiological and psychosocial developmental factors in adolescence and early adulthood which may contribute to this co-occurrence. METHOD: We studied the literature by means of PubMed, manuals and bibliographic references and used the search terms: 'adolescence', 'neurodevelopment', 'psychosis', 'schizophrenia', 'dopamine', 'substance (ab)use'. results Adolescence is a period of psychosocial challenges and changes in the brain which, in the case of predisposed persons, can increase the probability of the onset of both schizophrenia and substance abuse. The loss of exceptionally large numbers of dopaminergic neurons can lead to mesocortical hypofrontality combined with anhedonia and dysphoria, both of which are important risk factors for substance abuse. In turn, mesocortical hypofrontality can contribute to hyperactivity of the mesolimbic system, a condition associated with psychoses. We failed to find any other neurobiological explanations for the simultaneous occurrence of schizophrenia and substance abuse and for the fact that they both begin in adolescence and early adulthood. It should be noted, however, that there is a possible interaction between the gaba-glutamate and the dopaminergic neurotransmission. CONCLUSION: The partly overlapping pathogenesis and the simultaneous occurrence of drug abuse and schizophrenia call for integrated treatment. In treatment involving antipsychotics it is important to prevent the development of dysphoria and anhedonia which can adversely affect the patient's well-being and treatment compliance and even increase drug abuse.

[Gene-expression profiling in schizophrenia: an overview]. / Genexpressieprofilering bij schizofrenie: Een overzicht.

BACKGROUND: In recent molecular-biological research it has become possible to study the activity of genes. Gene expression is characterized, among other things, by its variability and its dependence on the developmental phase of the organism, on the cell- and tissue-type, and on environmental factors. Now we have a technique by which the activity of the 30,000 or more genes that make up the human genome can be measured in one go. This technique is known as 'microarray screening', 'high-throughput-analysis, or gene-expression profiling'. AIM: To describe some of the fundamentals of the gene-expression technique and to present an overview of the results of gene-expression studies of brain tissue taken from deceased patients. METHOD: We searched PubMed for relevant articles using the search terms 'schizophrenia', 'micro-array' and 'gene expression'. We located 10 articles/studies. RESULTS AND CONCLUSION: We conclude that gene-expression profiling has produced some evidence that several functional groups of genes are involved in schizophrenia (e.g. gene groups relating to synapses, metabolism, myelination and oligodendrocytes). Several of these genes are located on known chromosomal risk loci for schizophrenia. Together these findings support the theories that postulate that schizophrenia is caused by disturbances in synaptic stability and plasticity. There is some evidence that disturbances in myelination and fatty-acid metabolism may also play a role.

Adolescence, schizophrenia and drug abuse: a window of vulnerability.

OBJECTIVE: To discuss the neurobiological and psychosocial developmental factors in adolescence contributing to simultaneous onset and co-occurrence of psychosis and substance use disorders. METHOD: A review of the literature. RESULTS: Adolescence is a period with specific psychosocial challenges and specific changes in the brain that increase the probability of the onset of both psychosis and substance abuse, in predisposed people. In vulnerable adolescents it is proposed that an excessive pruning of dopaminergic neurones leads to mesocortical hypofrontality causing anhedonia and dysphoria. At the same time, anhedonia and dysphoria are important risk factors for the development of substance abuse. In turn, hypofrontality leads to a reduction in mesocortical feedback inhibition of the mesolimbic system resulting in aberrant salience and positive symptoms. Finally, the development of aberrant salience plays a role in both psychoses and craving. CONCLUSION: Attention should be paid to the interaction of drug abuse and schizophrenia and an integrated treatment is needed. Dysphoria and anhedonia in schizophrenic adolescents are important factors in treatment with antipsychotic medication, both in terms of patient satisfaction and in the prevention of substance abuse.