A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression.

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1ß and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾ 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine.

Twenty-one patients with schizophrenia who met criteria for neuroleptic treatment resistance or intolerance participated in a crossover, placebo-controlled, double-blind comparison of long-term typical neuroleptic and clozapine treatment. Clozapine significantly reduced total as well as positive and negative symptoms in comparison with both fluphenazine and placebo. Of the 21 patients, eight (38%) showed clozapine superiority on the basis of prospective response criteria. High levels of extrapyramidal side effects during fluphenazine treatment and later onset of illness were clinical predictors of clozapine superiority. Clozapine and fluphenazine equally reduced plasma homovanillic acid levels in comparison with placebo, although fluphenazine but not clozapine increased plasma prolactin level. A striking biologic difference between clozapine and fluphenazine was clozapine's enhancement of indexes of noradrenergic activity. Superior clozapine response was predicted by low ratios of cerebrospinal fluid homovanillic acid to 5-hydroxyindoleacetic acid, consistent with the notion that balance between dopaminergic and serotoninergic systems is important for clozapine's mechanism of action.

Sleep and sleep electroencephalogram in depressed patients treated with phenelzine.

BACKGROUND: The beneficial effect of antidepressant interventions has been proposed to depend on suppression of rapid eye movement (REM) sleep or inhibition of electroencephalographic (EEG) slow-wave activity (SWA) in non-REM sleep. Use of the monoamine oxidase inhibitor phenelzine sulfate can eliminate REM sleep. We studied the relation between REM sleep suppression and antidepressant response and the effect of phenelzine therapy on sleep EEG power spectra. METHODS: Open-labeled prescriptions of 30 to 90 mg of phenelzine were given to 11 patients with major depressive disorder (6 men and 5 women; mean age, 41.4 years); all were physically healthy. Mood, dream recall, sleep, sleep EEG, and ocular and muscular activity during sleep were studied before treatment and during the third and fifth weeks of pharmacotherapy. RESULTS: Six patients remitted from depression, 2 responded partially, and 3 showed no antidepressant response. Independent from clinical response, REM sleep was dramatically suppressed. On average, only 4.9 minutes of REM sleep was observed in treatment week 5, and it was completely absent in 6 patients. This effect was compensated for by increased stage 2 sleep. In non-REM sleep, EEG power was higher than at baseline between 16.25 and 25 Hz. Slow-wave activity (power within 0.75-4.5 Hz) and the exponential decline of SWA during sleep were not affected. CONCLUSIONS: Antidepressant response to phenelzine treatment does not depend on elimination of REM sleep or inhibition of SWA in non-REM sleep. In depressed patients, REM sleep is regulated independently from non-REM sleep and can be manipulated without altering the dynamics of SWA.

Increased numbers of CD5+ B lymphocytes in schizophrenic patients.

Autoimmune mechanisms have been postulated to play a role in the pathogenesis of schizophrenia. Recently, increased numbers of B lymphocytes expressing the CD5 (Leu-1) surface antigen have been observed in patients with certain autoimmune diseases. In the present study, approximately 30% of schizophrenic patients (11/34) were found by cytofluorometric methods to have similarly increased levels of circulating CD5+ B cells compared with 6% (2/33) of healthy individuals and 5% (1/20) of patients with bipolar affective disorder. In schizophrenic patients with a "high" CD5+ B-cell phenotype, the percentage of B cells expressing the CD5 surface marker (mean +/- SEM, 52.4% +/- 3.5%) was comparable to that reported for patients with rheumatoid arthritis and significantly greater than that reported for patients with bipolar affective disorder (25.7% +/- 2.5%) and healthy controls (31.0% +/- 1.8%). Schizophrenic patients with high levels of CD5+ B cells had increased numbers of total B cells compared with control subjects and patients with low levels of CD5+ B cells. An elevation in CD5+ B cells may delineate a subgroup of schizophrenic patients whose disease has an underlying autoimmune and/or genetic cause.

Circulating lymphocyte phenotypic surface markers in anxiety disorder patients and normal volunteers.

BACKGROUND: Although the relationship between stress and immune function is an area of active investigation, there have been few reports studying the relationship between anxiety disorders and the immune system. METHODS: This study employs flow cytometry to measure circulating lymphocyte phenotypic markers in 20 medication-free patients with panic disorder, 33 medication-free patients with generalized social phobia, and 32 healthy controls. RESULTS: Both patients with panic disorder and patients with social phobia had increased CD16 (natural killer) cell numbers. Panic disorder patients also had increased numbers of CD19 cells (B lymphocytes), human leukocyte antigen (HLA)-DR-presenting cells, and more cells with the combination of HLA-DR and CD19 surface markers (B lymphocytes with HLA-DR on their surface). CONCLUSIONS: These preliminary data suggest that subjects with panic disorder may have alterations in circulating lymphocyte profiles.

The effects of lithium on ex vivo cytokine production.

BACKGROUND: Studies suggest that lithium may have profound immunomodulatory effects in animal models as well as in humans. METHODS: In this study, whole blood cultures from normal control subjects were established for 5 days and the effects of lithium on cytokine production were investigated. Because many of lithium's actions have been postulated to be modulated through phosphoinositide (PI), protein kinase C (PKC) and cyclic adenosine monophosphate (c-AMP) signaling pathways, the effects of myo-inositol and prostaglandin E(2), alone or in combination with lithium, were also investigated. RESULTS: We found that lithium caused an increase in interleukin-4 and interleukin-10 levels, traditionally classified as T-helper lymphocyte type-2 cytokines, and a decrease in interleukin-2 and interferon-gamma levels, traditionally classified as T-helper lymphocyte type-1 (TH-1) cytokines. This shift cannot be fully explained by lithium's actions on the PI, PKC, or c-AMP messenger systems. CONCLUSIONS: Monocytes exposed to lithium in the presence of a mitogen for 5 days produced a shift toward the production of TH-2 cytokines and away from the production of TH-1 cytokines. The study suggests that lithium may have complex time-dependent effects on immune function.

The effects of prolonged lithium exposure on the immune system of normal control subjects: serial serum soluble interleukin-2 receptor and antithyroid antibody measurements.

The purpose of this study was to begin evaluating the effects of lithium carbonate on in vivo immune function in normal controls. We postulated that lithium carbonate would stimulate lymphocytes but would not affect the production of antithyroid antibodies. Twenty-seven normal controls had blood samples drawn for measurements of serum soluble interleukin-2 receptors (SIL-2Rs), antithyroglobulin antibodies, and antimicrosomal antibodies prior to and after approximately 1 and 4 weeks of treatment with lithium carbonate at therapeutic blood levels. Subjects had a small but statistically significant increase in serum SIL-2Rs after 4 weeks of lithium treatment (446.3 +/- 177.2 U/ml versus 497.6 +/- 232.3 U/ml, p = 0.033). There was no increase in the prevalence of antithyroglobulin or antimicrosomal antibodies with lithium treatment nor did lithium act as an adjuvant to increase the titers in subjects with preexisting antithyroid antibodies.

Trait contributions of complex dysregulated behavioral organization in schizophrenic patients.

BACKGROUND: The "temporal architecture" of behavior is a construct that can be used to quantify the structure of behavioral sequences in the temporal domain-for example, by using a two-choice prediction task to investigate how past responses, stimuli, and outcomes influence the decision-making process. Using this task, previous investigations of the temporal architecture of the behavior in schizophrenic patients have identified an increased frequency of alternating highly predictable and highly unpredictable response sequences in the same test session in the same patient. Here, the hypothesis is tested that this dysregulation is stable over time and independent of psychosocial factors and symptomatic fluctuations. METHODS: Ninety-one schizophrenic patients were tested on a 128 trial version of the two-choice prediction task; of those, 58 subjects completed a retest session 40 days later. Three sets of measures were obtained: simple response biases, dynamical entropy, and mutual information functions. These measures were subjected to a factor analysis, and the reliability of the resulting factors was examined. RESULTS: First, three factors were obtained, which quantify 1) the level of dysregulation on this task; 2) the extent to which a win-stay/lose-shift strategy was used; and 3) the amount of simple response perseveration. Second, Crohnbach alpha for these factors was .699, .721, and .458, respectively. Third, there were no significant differences in the level of these factors within individual patients at the two time points. Fourth, neither symptom measures (Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms subscale scores) nor psychosocial or clinical variables (age, gender, illness duration, medication status) were able to predict the level of these factors at test or at retest. CONCLUSIONS: These results support the hypothesis that the fundamental dysregulation of the temporal architecture of behavior in schizophrenic patients is stable across time and independent of symptomatic status. Future studies will examine the heritability of this dysfunction.

Neuroendocrine effects of ovine corticotropin-releasing hormone in panic disorder patients.

A number of neuroendocrine abnormalities have been reported in panic disorder patients: the most extensively studied being disturbances of hypothalamic-pituitary-adrenal function (Curtis et al. 1982; Leiberman et al. 1983; Uhde et al. 1988). The recent sequencing and synthesis of corticotropin-releasing hormone now allows direct testing of pituitary responsivity to this neuropeptide in affective and panic disorder patients (Holsboer et al. 1984; Gold et al. 1986; Roy-Byrne et al. 1986; Holsboer et al. 1987; Risch et al. 1988). We report the effects of intravenously administered ovine corticotropin-releasing hormone (0.03 micrograms/kg) on plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol in a small group of panic disorder patients and age- and sex-matched normal controls.

The effects of physostigmine infusion on patients with panic disorder.

Nine patients who met both DSM-III and RDC criteria for panic disorder and nine age-matched normal controls received infusions of physostigmine. The patients and normal controls did not differ in either their self-reported or the observer-reported ratings of anxiety, mood, or activation. The two subject groups also did not differ in blood pressure, pulse, or cortisol responses to physostigmine. Physostigmine did not provoke panic attacks in either the control or patients groups.

Sleep electroencephalographic response to muscarinic and serotonin1A receptor probes in patients with major depression and in normal controls.

BACKGROUND: To test the hypothesis that depression is associated with an increased ratio of cholinergic to serotonergic neurotransmission, we compared the effects of pilocarpine, a muscarinic agonist, and ipsapirone, a serotonin (5-HT)1A agonist, on electroencephalographic (EEG) sleep in depressed and healthy subjects. We hypothesized, adopting the reciprocal interaction model, that the effects on REM sleep of these probes within the same individuals are negatively correlated and unmask neurobiological changes in depression. METHODS: Polysomnographic recordings were obtained in 12 unmedicated patients with a current major depression and 12 normal controls. They received placebo, pilocarpine 25 mg, or ipsapirone 10 mg (orally, 15 min before bedtime, after premedication with the peripheral anticholinergic probanthine 30 mg, double blind, counterbalanced) on three occasions. RESULTS: Pilocarpine shortened and ipsapirone prolonged REM latency equally in both groups. These effects were not correlated. Pilocarpine decreased slow-wave sleep and EEG delta power during the first nonREM episode more in controls than in patients, and enhanced EEG sigma power equally in both groups. Ipsapirone had no significant effects on EEG power. CONCLUSION: These data do not support the postulate of muscarinic receptor up-regulation and 5-HT1A receptor down-regulation in depression. The significance of blunted delta power suppression in patients following pilocarpine warrants further investigations.

Increased serum soluble interleukin-2 receptors in Caucasian and Korean schizophrenic patients.

Recent studies have identified immunologic abnormalities in some schizophrenic subjects. This experiment replicates previous findings that serum soluble interleukin-2 receptors (SIL-2Rs) are elevated in schizophrenic patients, and is the first study to describe this phenomenon in non-Caucasian patients. Despite differences between Korean and Caucasian schizophrenic patients in absolute serum SIL-2R levels, both groups were significantly elevated when compared with their respective ethnic control groups (477 +/- 171 U/ml versus 354 +/- 172 U/ml and 763 +/- 347 U/ml versus 567 +/- 231 U/ml, respectively). Neither age, gender, medication status, nor duration of illness correlated with SIL-2R levels. These findings are further evidence that immune activation is present, regardless of ethnic origin, in some schizophrenic patients.

Is placebo response the same as drug response in panic disorder?

OBJECTIVE: The authors used seven definitions of response in panic disorder to compare patient-rated improvements in quality of life between patients with panic disorder who responded to sertraline and those who responded to placebo. METHOD: They combined and examined data from two multicenter, randomized, double-blind, parallel-group, flexible-dose studies of panic disorder (N=302). RESULTS: Significant differences in quality of life between patients who responded to sertraline and those who responded to placebo were apparent across all the definitions of clinical response. CONCLUSIONS: Patients who respond to placebo in panic disorder treatment studies may show symptom relief but may not experience improvement in quality of life. Determinations of quality of life should be included as components of both standard clinical assessment and clinical treatment studies of patients with panic disorder.

Blunted growth hormone response to peripheral infusion of human growth hormone-releasing factor in patients with panic disorder.

Patients with panic disorder (N = 11) and age- and sex-matched normal control subjects (N = 11) were challenged with human growth hormone-releasing factor (GH-RF) (1 microgram/kg i.v.) or placebo in random order. The control subjects had significantly increased plasma growth hormone (GH) levels after GH-RF infusion whereas panic disorder patients did not. At 15 and 30 minutes after GH-RF infusion, GH concentrations were significantly higher in the control subjects than in the patients. These findings with GH-RF extend findings from earlier reports that patients with panic disorder show blunted GH response to phobic stimulation and clonidine.

Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population.

OBJECTIVE: The authors' goal was to evaluate the association between impairment in daily function and subsyndromal depressive symptoms as well as major depression to determine the economic and societal significance of these conditions. METHOD: Using 12-month prevalence data gathered by the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Program (ECA), based on responses to the NIMH Diagnostic Interview Schedule, the authors divided the 2,393 subjects from the Los Angeles ECA site into three groups: subjects with subsyndromal depressive symptoms (N = 270), major depression (N = 102), and no depressive disorder or symptoms (N = 2,021). The groups were compared on 10 domains of functional outcome and well-being. RESULTS: Significantly more subjects with depressive symptoms than subjects who had no disorder reported high levels of household strain, social irritability, and financial strain as well as limitations in physical or job functioning, restricted activity days, bed days, and poor health status. Significantly more subjects with major depression than subjects with no disorder reported major financial losses, bed days, high levels of financial strain, limitations in physical or job functioning, and poor health status. Except for lower self-ratings of health status, no significant differences were found between subjects with subsyndromal symptoms and those with major depression. CONCLUSIONS: Significantly more people with subsyndromal depressive symptoms or major depression reported impairment in eight of 10 functional domains than did subjects with no disorder. The high 1-year prevalence of subsyndromal depressive symptoms, combined with the associated functional impairment, emphasizes the clinical and public health importance and need for additional investigations into these symptoms.

Beneficial effects of nalmefene augmentation in neuroleptic-stabilized schizophrenic patients.

It was postulated that chronic blockade of the opioid system in neuroleptic-stabilized schizophrenic patients would have a beneficial behavioral effect. Eleven neuroleptic-stabilized psychotic inpatients received augmentation with nalmefene for an average of 36.7 days in a double-blind placebo-controlled study. The patients exhibited significant reductions in Bunney-Hamburg psychosis ratings and the Brief Psychiatric Rating Scale thinking disturbance subscale during the augmentation period. This study presents preliminary data supporting the hypothesis that chronic augmentation of neuroleptic-stabilized schizophrenic patients with opiate antagonists is beneficial.

Analysis of GNAZ gene polymorphism in bipolar affective disorder.

Evidence for a bipolar disorder (BPD) susceptibility locus on chromosome 22q11 has been provided in several studies. One candidate gene that maps to this region is the G-protein alpha subunit gene Galphaz (GNAZ). We have identified a common silent polymorphism in GNAZ exon 2 by single strand conformation polymorphism analysis. The frequency of this polymorphism was determined in a control population (n=84) and in patients with BPD (n=88). The data showed a statistical trend toward a difference in the distribution of alleles in patients with BPD compared with control subjects (chi square=3.2, 1 df, P=0.073, two-tailed). No significant difference was detected when the GNAZ polymorphism was analyzed in control subjects and schizophrenia patients (n=63, P=0.92). These data continue to provide some support for a BPD susceptibility gene on 22q11, possibly in linkage disequilibrium with the GNAZ 309 polymorphism.

Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22.

Velo-cardio-facial syndrome (VCFS) is a congenital anomaly characterized by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities, that results from a microdeletion of chromosome 22q11. An increased prevalence of psychiatric illness has been observed, with both schizophrenia and bipolar disorder commonly being diagnosed. For these reasons, the VCFS region is an interesting candidate region for bipolar disorder. We examined this region in 17 bipolar families from three populations: 13 families from the general North American population (University of California, San Diego/University of British Columbia, UCSD/UBC), three larger families from New York, and a portion of Old Order Amish pedigree 110. Three microsatellite markers spanning 13 cM around the VCFS region were genotyped in all the families. A maximum lod score of 2.51 was obtained in the UCSD/UBC families under a dominant model at D22S303. In the combined family set, maximum lod scores of 1.68 and 1.28 were obtained at this marker under dominant and recessive models, respectively. Four additional markers were subsequently typed in selected positive families, and yielded positive lods at 6 of 7 markers spanning 18 cM in this region. Nonparametric, multipoint analyses using the affected pedigree member (APM) method also yielded suggestive evidence for linkage in both the UCSD/UBC family set (P = 0.0024) and in the combined families (P = 0.017). Affected sibpair analyses were similarly positive in the UCSD/UBC families (P = 0.017), and in the combined families (P = 0.004). These results are suggestive of a possible locus for bipolar disorder near the VCFS region on chromosome 22.