Marieke J.H. Begemann

Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update

BACKGROUND The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest because more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory agents to improve symptoms of schizophrenia. This study provides an update regarding the efficacy of anti-inflammatory agents on schizophrenic symptoms in clinical studies performed so far. METHODS An electronic search was performed using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. Only randomized, double-blind, placebo-controlled studies that investigated clinical outcome were included. RESULTS Our search yielded 26 double-blind randomized controlled trials that provided information on the efficacy on symptom severity of the following components: aspirin, celecoxib, davunetide, fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06-0.537, I(2) = 0), estrogens (ES: 0.51, n = 262, 95% CI: 0.043-0.972, I(2) = 69%), and NAC (ES: 0.45, n = 140, 95% CI: 0.112-0.779) showed significant effects. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect. CONCLUSION The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.

Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis.

OBJECTIVE Mounting evidence suggests that inflammation is involved in the pathogenesis of schizophrenia. This evidence implies that anti-inflammatory agents are potentially useful therapeutic strategies in schizophrenia. This article quantitatively summarizes the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) to augment antipsychotic treatment to reduce schizophrenia symptom severity. DATA SOURCES An electronic search was performed using MEDLINE, Embase, the National Institutes of Health Web site clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. The following basic search terms were used: schizophrenia, nonsteroidal anti-inflammatory drug, and NSAID together with the name of each specific NSAID (ibuprofen, diclofenac, naproxen sodium, and acetylsalicylic acid). We applied no year or language restrictions. STUDY SELECTION Studies were selected if they met the following inclusion criteria: (1) randomized, double-blind, placebo-controlled trials regarding augmentation of antipsychotic medication with an NSAID, (2) patients included had a diagnosis of a schizophrenia spectrum disorder according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, and (3) studies reported sufficient information to compute common effect size statistics, or corresponding authors could supply these data upon request. DATA EXTRACTION The primary outcome measure was the mean change in total score on the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures included positive and negative symptom subscores of the PANSS. RESULTS We could include 5 double-blind, randomized, placebo-controlled trials, reporting on 264 patients. Four studies applied celecoxib, and 1 used acetylsalicylic acid. We found a mean effect size of 0.43, which was significant at P = .02 in favor of NSAIDs on total symptom severity. For positive symptom severity, the mean standardized difference was 0.34 (P = .02). For severity of negative symptoms the mean standardized difference was 0.26 (P = .03). CONCLUSIONS These results suggest that NSAID augmentation could be a potentially useful strategy to reduce symptom severity in schizophrenia. As these are the first studies on a relatively new strategy and the included sample size is modest, these results should be interpreted with caution. However, augmentation with acetylsalicylic acid may have the additional benefit of reducing cardiac and cancer mortality in schizophrenia. We therefore believe that application of NSAIDs in schizophrenia deserves further investigation as augmentation of antipsychotic treatment and reducing comorbid somatic diseases.

Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

BACKGROUND When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder. METHODS Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedgess g). RESULTS Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies. CONCLUSIONS Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

Estrogen augmentation in schizophrenia: a quantitative review of current evidence.

BACKGROUND Sex differences in the incidence, onset and course of schizophrenia have led to the hypothesis that estrogens play a protective role in the pathophysiology of this disorder. Several trials have assessed the potential of estrogens in reducing schizophrenia symptoms, showing inconsistent results. This quantitative review summarizes available evidence on the efficacy of estrogens in the treatment of schizophrenia. METHODS Only double-blind, placebo-controlled, randomized studies were included. Primary outcome measure was total symptom severity, secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated for individual studies and, if possible, pooled in meta-analyses to obtain combined, weighted effect sizes (Hedgess g). RESULTS Superior efficacy was found for estrogen treatment in female patients (four RCTs, 214 patients) on total symptom severity (Hedgess g=0.66), although heterogeneity was moderate to high. Estrogens were also superior in reducing positive (Hedgess g=0.54) and negative symptoms (Hedgess g=0.34), with low heterogeneity. As the included studies applied different forms of estrogens, a separate analysis was conducted on the trials applying estradiol (three RCTs, 170 patients). Even larger effect sizes were found for total symptom severity (Hedgess g=0.79), positive (Hedgess g=0.57) and negative symptoms (Hedgess g=0.45), with reduced heterogeneity. Estrogen treatment in male patients (one study, 53 patients) was not superior to placebo. CONCLUSIONS Our results suggest that estrogens, especially estradiol, could be an effective augmentation strategy in the treatment of women with schizophrenia. However, future larger trials are needed before recommendations on clinical applications can be made.

Cortical thickness in individuals with non-clinical and clinical psychotic symptoms

Symptoms that are linked to psychosis are also experienced by individuals who are not in need of care. In the present study, cortical thickness was investigated in these individuals. Fifty individuals with non-clinical auditory verbal hallucinations (most of them also experienced other non-clinical psychotic symptoms), 50 patients with a psychotic disorder and auditory verbal hallucinations, and 50 healthy control subjects underwent structural magnetic resonance imaging. Data were analysed using FreeSurfer. Cortical thickness in the pars orbitalis, paracentral lobule, fusiform gyrus and inferior temporal gyrus was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in control subjects. The patients also showed thinning in widespread additional areas compared to the two other groups, whereas both hallucinating groups showed similar levels of thinning in the insula. Ranking the levels of cortical thickness per brain region across groups revealed that for 88% of brain regions, cortical thickness was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in controls. These findings show that individuals with non-clinical psychotic symptoms show a similar but less pronounced pattern of cortical thinning as patients with a psychotic disorder, which is suggestive of a similar, but milder underlying pathophysiology in this group compared to the psychosis group.

The influence of stimulus detection on activation patterns during auditory hallucinations

INTRODUCTION Neuroimaging studies investigating auditory verbal hallucinations (AVH) have revealed involvement of several cortical structures. These findings may however be biased by brain activity related to stimulus detection and motor processes associated with the task to indicate the presence of AVH. Disentangling brain activation specifically related to AVH and to additional cognitive processes may help focus on the true neuronal substrates of AVH and strengthen the development of new focal treatment strategies. METHODS Brain activation during AVH as indicated by button press was compared to brain activation during auditory stimulus detection indicated by button press. We performed two neuroimaging meta-analyses, assessing 10 AVH and 11 auditory stimulus detection studies. A random-effects activation likelihood estimation was performed using GingerALE to assess commonalities and differences across AVH and stimulus detection studies. RESULTS Activity in the claustrum, pulvinar area, medial geniculum body, pyramis, culmen, putamen, insula, and parahippocampal, medial frontal, precentral, postcentral, superior temporal and right inferior frontal gyri was found to be specifically related to AVH. The pars opercularis of the left inferior frontal gyrus and the left transverse temporal gyrus were activated to a similar extent during AVH and auditory stimulus detection. DISCUSSION Development of new focal treatment strategies for AVH may focus on the areas uniquely activated in the AVH analysis. The pars opercularis and the transverse temporal gyrus may not be directly involved in the experience of AVH itself, but rather in auditory stimulus detection.

The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis

Recognizing the robust sex differences in schizophrenia prevalence, the selective estrogen receptor modulator (SERM) raloxifene is a likely candidate for augmentation therapy in this disorder. Therefore, a systematic search was performed using PubMed (Medline), Embase, PsychInfo, and Cochrane Database of Systematic Reviews. Randomized controlled trials investigating the effect of raloxifene in schizophrenia spectrum disorders were included in the quantitative analyses. Outcome measures were psychotic symptom severity, depression, and cognition. Meta-analyses were performed using Comprehensive Meta-Analysis software. A random-effects model was used to compute overall weighted effect sizes in Hedges’ g. Nine studies were included, investigating 561 patients with a schizophrenia spectrum disorder. Raloxifene was superior to placebo in improving total symptom severity (N = 482; Hedge’s g = .57, p = 0.009), as well as positive (N = 561; Hedge’s g = 0.32, p = 0.02), negative (N = 561; Hedge’s g = 0.40, p = 0.02), and general (N = 526; Hedge’s g = 0.46, p = 0.01) subscales, as measured by the Positive and Negative Syndrome Scale. No significant effects were found for comorbid depression and cognitive functioning. Altogether, these results confirm the potential of raloxifene augmentation in the treatment of schizophrenia.

Auditory hallucinations across the lifespan: a systematic review and meta-analysis.

BACKGROUND Auditory Hallucinations (AH) are nowadays regarded as symptoms following a continuum; from a (transient) phenomenon in healthy individuals on one end to a symptom of (psychiatric) illnesses at the other. An accumulating number of epidemiological studies focused on the prevalence of AH in the general population, but results vary widely. The current meta-analysis aims to synthesize existing evidence on lifetime prevalence of AH across the lifespan. METHODS We conducted a quantitative review and meta-analysis according to PRISMA guidelines. Studies were combined to calculate a mean lifetime general population AH prevalence rate. Moreover, prevalences were calculated for four age groups: children (5-12 years), adolescents (13-17 years), adults (18-60 years) and elderly (⩾60 years). RESULTS We retrieved 25 study samples including 84 711 participants. Mean lifetime prevalence rate of AH was 9.6% (95% CI 6.7-13.6%). The mean lifetime prevalence was similar in children (12.7%) and adolescents (12.4%), but these two groups differed significantly from the adults (5.8%) and the elderly (4.5%). Significant heterogeneity indicated that there is still dispersion in true prevalence rates between studies, even within the different age categories. CONCLUSIONS Current meta-analysis shows that AH are quite common (up to one in ten individuals) in the general population during lifetime, with children and adolescents reporting these experiences significantly more often compared with adults and elderly. Large follow-up studies on the longitudinal course of AH are needed to reveal associated risk and resilience factors.

Efficacy of EEG neurofeedback in psychiatry: A comprehensive overview and meta-analysis

Background: This article provides a comprehensive overview of studies investigating the efficacy of EEG neurofeedback in the treatment of psychiatric disorders. Method: Only studies comparing neurofeedback to a control group (passive/semi-active, placebo, or drug treatment) were included. Effect sizes were calculated for individual studies and when possible combined in meta-analysis (Hedges’s g). Results: We retrieved 30 studies including 1171 participants, evaluating neurofeedback for ADHD, autism, OCD, GAD and depression. For ADHD, combining nineteen trials in meta-analysis yielded small to medium effect sizes for symptoms of inattention, hyperactivity and impulsivity. Subgroup analyses showed that neurofeedback was superior to passive/semi-active treatment (medium effects), while efficacy was similar to placebo (only one study) and drug treatment. For ASD, combining five studies resulted in a superior effect of neurofeedback in reducing general symptomatology; subgroup analyses showed that neurofeedback was more effective than passive/semi-active treatment (four studies) and placebo (based on a single study). Three OCD studies showed varying results, depending on the type of control group used. Two GAD studies found neurofeedback to be similar or inferior to EMG biofeedback. One study on depression showed a large effect for neurofeedback when compared to semi-active treatment. Conclusion: Although 30 studies could be included, our review of the literature reveals serious limitations of the body of research currently performed. Therefore at present, it cannot be concluded that EEG neurofeedback can be regarded as an evidence-based treatment for ADHD, ASD, OCD, GAD and depression. Large, well-designed studies are needed to elucidate whether neurofeedback is a viable treatment option in the field of psychiatry. Correspondence to: M.J.H. Begemann, MSc, Department of Psychiatry, University Medical Center Utrecht (UMCU), Heidelberglaan 100, 3584 CX Utrecht, Netherlands, Tel: +31887556370; E-mail: M.J.H.Begemann@umcutrecht.nl

Relationship between neuroticism, childhood trauma and cognitive-affective responses to auditory verbal hallucinations

Neuroticism has been shown to adversely influence the development and outcome of psychosis. However, how this personality trait associates with the individual’s responses to psychotic symptoms is less well known. Auditory verbal hallucinations (AVHs) have been reported by patients with psychosis and non-clinical individuals. There is evidence that voice-hearers who are more distressed by and resistant against the voices, as well as those who appraise the voices as malevolent and powerful, have poorer outcome. This study aimed to examine the mechanistic association of neuroticism with the cognitive-affective reactions to AVH. We assessed 40 psychotic patients experiencing frequent AVHs, 135 non-clinical participants experiencing frequent AVHs, and 126 healthy individuals. In both clinical and non-clinical voice-hearers alike, a higher level of neuroticism was associated with more distress and behavioral resistance in response to AVHs, as well as a stronger tendency to perceive voices as malevolent and powerful. Neuroticism fully mediated the found associations between childhood trauma and the individuals’ cognitive-affective reactions to voices. Our results supported the role of neurotic personality in shaping maladaptive reactions to voices. Neuroticism may also serve as a putative mechanism linking childhood trauma and psychological reactions to voices. Implications for psychological models of hallucinations are discussed.