Iris E. Sommer

Should We Expand the Toolbox of Psychiatric Treatment Methods to Include Repetitive Transcranial Magnetic Stimulation (rTMS)? A Meta-Analysis of the Efficacy of rTMS in Psychiatric Disorders

OBJECTIVE Repetitive transcranial magnetic stimulation (rTMS) is a safe treatment method with few side effects. However, efficacy for various psychiatric disorders is currently not clear. DATA SOURCES A literature search was performed from 1966 through October 2008 using PubMed, Ovid Medline, Embase Psychiatry, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and PsycINFO. The following search terms were used: transcranial magnetic stimulation, TMS, repetitive TMS, psychiatry, mental disorder, psychiatric disorder, anxiety disorder, attention-deficit hyperactivity disorder, bipolar disorder, catatonia, mania, depression, obsessive-compulsive disorder, psychosis, posttraumatic stress disorder, schizophrenia, Tourettes syndrome, bulimia nervosa, and addiction. STUDY SELECTION Data were obtained from randomized, sham-controlled studies of rTMS treatment for depression (34 studies), auditory verbal hallucinations (AVH, 7 studies), negative symptoms in schizophrenia (7 studies), and obsessive-compulsive disorder (OCD, 3 studies). Studies of rTMS versus electroconvulsive treatment (ECT, 6 studies) for depression were meta-analyzed. DATA EXTRACTION Standardized mean effect sizes of rTMS versus sham were computed based on pretreatment-posttreatment comparisons. DATA SYNTHESIS The mean weighted effect size of rTMS versus sham for depression was 0.55 (P < .001). Monotherapy with rTMS was more effective than rTMS as adjunctive to antidepressant medication. ECT was superior to rTMS in the treatment of depression (mean weighted effect size -0.47, P = .004). In the treatment of AVH, rTMS was superior to sham treatment, with a mean weighted effect size of 0.54 (P < .001). The mean weighted effect size for rTMS versus sham in the treatment of negative symptoms in schizophrenia was 0.39 (P = .11) and for OCD, 0.15 (P = .52). Side effects were mild, yet more prevalent with high-frequency rTMS at frontal locations. CONCLUSIONS It is time to provide rTMS as a clinical treatment method for depression, for auditory verbal hallucinations, and possibly for negative symptoms. We do not recommend rTMS for the treatment of OCD.

The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls

Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease.

Language lateralization in schizophrenia, an fMRI study

Anatomical studies have shown that cerebral asymmetry is reduced in schizophrenia. Functional asymmetry appears to be reduced also, as was shown with dichotic listening studies. These studies, however, have not revealed whether reduced lateralization is the result of decreased language activity of the left hemisphere or whether it is the consequence of increased language-related activity in the right hemisphere. To elucidate this, we examined hemispheric dominance for language processing by means of functional MRI. Twelve schizophrenic patients and twelve healthy controls were scanned while they were engaged in a verb-generation and a semantic decision task. Activation was measured bilaterally in the frontal, temporal and temporo-parietal language areas, and a laterality index was derived from activity in these regions of interest in the left and the right hemispheres. Clinical symptoms were rated at the time of scanning. The results indicate that language processing is less lateralized in patients than in controls (a mean laterality index of 0.35 versus 0.63, respectively, difference p<0.01). Analysis of variance of the extent of activity, i.e. numbers of active voxels, revealed a significant hemisphere by group interaction (F(1,22)=11.2, p<0.001), which was due to increased activation in the right hemisphere of the patients (post hoc t-test p<0.05). We found no evidence of reduced activity in the left hemisphere. Further analysis of clinical symptoms rated prior to scanning revealed that decreased language lateralization was associated with more severe hallucinations (r=-0.54, p<0.05). We postulate that decreased language lateralization in schizophrenia may result from failure to inhibit the right hemisphere.

Auditory verbal hallucinations predominantly activate the right inferior frontal area.

The pathophysiology of auditory verbal hallucinations (AVH) is largely unknown. Several functional imaging studies have measured cerebral activation during these hallucinations, but sample sizes were relatively small (one to eight subjects) and findings inconsistent. In this study cerebral activation was measured using fMRI in 24 psychotic patients while they experienced AVH in the scanner and, in another session, while they silently generated words. All patients were right handed and diagnosed with schizophrenia, schizo-affective disorder or psychotic disorder not otherwise specified. Group analysis for AVH revealed activation in the right homologue of Brocas area, bilateral insula, bilateral supramarginal gyri and right superior temporal gyrus. Brocas area and left superior temporal gyrus were not activated. Group analysis for word generation in these patients yielded activation in Brocas and Wernickes areas and to a lesser degree their right-sided homologues, bilateral insula and anterior cingulate gyri. Lateralization of activity during AVH was not correlated with language lateralization, but rather with the degree to which the content of the hallucinations had a negative emotional valence. The main difference between cerebral activity during AVH and activity during normal inner speech appears to be the lateralization. The predominant engagement of the right inferior frontal area during AVH may be related to the typical low semantic complexity and negative emotional content.

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.

Combined analysis of language tasks in fMRI improves assessment of hemispheric dominance for language functions in individual subjects.

Recent advances in functional neuroimaging techniques have prompted an increase in the number of studies investigating lateralization of language functions. One of the problems in relating findings of various studies to one another is the diversity of reported results. This may be due to differences in the tasks that are used to stimulate language processing regions and in the control tasks, as well as differences in the way imaging data are analyzed,in particular the threshold for significance of signal change. We present a simple method to assess language lateralization that allows for some variation of tasks and statistical thresholding, but at the same time yields reliable and reproducible results. Images acquired during a set of word-comprehension and -production tasks are analyzed conjointly. As opposed to the use of any one particular task, this combined task analysis (CTA) approach is geared toward identifying language regions that are involved in generic language functions rather than regions that are involved in functions that are specific to a single task. In two experiments CTA is compared to single-task analysis in healthy right-handed males. In a third experiment left-handed males were examined. Results indicate that CTA: (1) improves detection of language-related brain activity in individual subjects and (2) yields a high language laterality index (LI) in right-handed males with a small variance across subjects. The high LI matches the strong left-hemisphere dominance for language that is typical for these subjects as reported in neuropsychological and clinical tests in other studies. In the left-handed subjects dominance was found either in the left (n = 4) or the right (n = 1) hemisphere or was absent (n = 3). The LI derived from CTA is more consistent across statistical thresholds for significance of signal change in fMRI analysis than in individual-task analysis. Also, the CTA results are very similar to those obtained with conjunction analysis of the same data.

The same or different? A phenomenological comparison of auditory verbal hallucinations in healthy and psychotic individuals.

OBJECTIVE Whereas auditory verbal hallucinations (AVHs) are most characteristic of schizophrenia, their presence has frequently been described in a continuum, ranging from severely psychotic patients to schizotypal personality disorder patients to otherwise healthy participants. It remains unclear whether AVHs at the outer borders of this spectrum are indeed the same phenomenon. Furthermore, specific characteristics of AVHs may be important indicators of a psychotic disorder. METHOD To investigate differences and similarities in AVHs in psychotic and nonpsychotic individuals, the phenomenology of AVHs in 118 psychotic outpatients was compared to that in 111 otherwise healthy individuals, both experiencing AVHs at least once a month. The study was performed between September 2007 and March 2010 at the University Medical Center, Utrecht, the Netherlands. Characteristics of AVHs were quantified using the Psychotic Symptoms Rating Scales Auditory Hallucinations subscale. RESULTS The perceived location of voices (inside/outside the head), the number of voices, loudness, and personification did not differentiate between psychotic and healthy individuals. The most prominent differences between AVHs in healthy and psychotic individuals were the emotional valence of the content, the frequency of AVHs, and the control subjects had over their AVHs (all P values < .001). Age at onset of AVHs was at a significantly younger age in the healthy individuals (P < .001). In our sample, the negative emotional valence of the content of AVHs could accurately predict the presence of a psychotic disorder in 88% of the participants. CONCLUSIONS We cannot ascertain whether AVHs at the outer borders of the spectrum should be considered the same phenomenon, as there are both similarities and differences. The much younger age at onset of AVHs in the healthy subjects compared to that in psychotic patients may suggest a different pathophysiology. The high predictive value of the emotional content of voices implies that inquiring after the emotional content of AVHs may be a crucial step in the diagnosis of psychotic disorders in individuals hearing voices.

Healthy Individuals With Auditory Verbal Hallucinations; Who Are They? Psychiatric Assessments of a Selected Sample of 103 Subjects

Epidemiological studies suggest that auditory verbal hallucinations (AVH) occur in approximately 10%-15% of the general population, of whom only a small proportion has a clinically relevant psychotic disorder. It is unclear whether these hallucinations occur as an isolated phenomenon or if AVH in nonclinical individuals are part of a more general susceptibility to schizophrenia. For this study, 103 healthy individuals with frequent AVH were compared with 60 controls matched for sex, age, and education. All participants were examined by a psychiatrist using standardized diagnostic interviews and questionnaires. The individuals with AVH did not have clinically defined delusions, disorganization, or negative or catatonic symptoms, nor did they meet criteria for cluster A personality disorder. However, their global level of functioning was lower than in the controls and there was a pronounced increase on all subclusters of the Schizotypal Personality Questionnaire (SPQ) and the Peters Delusion Inventory, indicating a general increased schizotypal and delusional tendency in the hallucinating subjects. History of childhood trauma and family history of axis I disorders were also more prevalent in these individuals. We showed that higher SPQ scores, lower education, and higher family loading for psychiatric disorders, but not presence of AVH, were associated with lower global functioning. Our data suggest that AVH in otherwise healthy individuals are not an isolated phenomenon but part of a general vulnerability for schizophrenia.

Sex differences in handedness, asymmetry of the Planum Temporale and functional language lateralization

Many studies have investigated sex differences in language lateralization. Despite the large number of investigations, controversy about the presence of sex differences in lateralization remains. This study aims to provide a complete overview of sex differences in several reflections of language lateralization: handedness, asymmetry of the Planum Temporale (PT) and functional lateralization of language, measured by asymmetric performance on dichotic listening tests (Right Ear Advantage) and asymmetry of language activation as measured with functional imaging techniques. Meta-analysis of studies that assessed handedness in males and females yielded more left-handedness in males (mean weighted odds ratio: 1.25, p<0.001). Meta-analysis of studies on PT asymmetry yielded no sex difference (Hedges g=-0.11, p=0.68). Results of the meta-analysis on dichotic listening studies also retrieved no sex difference in lateralization (Hedges g=0.09, p=0.18). When the studies were subdivided according to the paradigm they applied, studies that used the consonant-vowel task yielded a sex difference favouring males, while studies that applied other paradigms yielded no sex difference. The subdivision into applied paradigm largely overlapped with the subdivision into studies that did or did not focus on sex differences as their main topic. The observed sex effect may therefore be caused by publication bias. Meta-analysis of functional imaging studies yielded no sex difference (Hedges g=0.01, p=0.73) in language lateralization. Sub-analyses of studies that applied different paradigms all yielded no sex difference. In conclusion, males are more frequently non-right handed than females, but there is no sex difference in asymmetries of the Planum Temporale, dichotic listening or functional imaging findings during language tasks.

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.