Neurochemical regulation of auditory information processing studied with EEG/MEG: application to schizophrenia

Cognitive impairments of attention, memory and executive functions are a fundamental feature of the pathophysiology of schizophrenia. The neurophysiological and neurochemical changes in the auditory cortex are shown to underlie cognitive impairmentsin schizophrenia patients. Functional state of the neural substrate of auditory information processing could be objectively and non-invasively probed with auditory event-related potentials (ERPs) and event- related fields (ERFs). In the current work, we explored the neurochemical effect on the neural origins of auditory information processing in relation to schizophrenia. By means of ERPs/ERFs we aimed to determine how neural substrates of auditory information processing are modulated by antipsychotic medication in schizophrenia spectrum patients (Studies I, II) and by neuropharmacological challenges in healthy human subjects (Studies III, IV). First, with auditory ERPs we investigated the effects of olanzapine (Study I) and risperidone (Study II) in a group of patients with schizophrenia spectrum disorders. After 2 and 4 weeks of treatment, olanzapine has no significant effects on mismatch negativity(MMN) and P300, which, as it has been suggested, respectively reflect preattentive and attention-dependent information processing. After 2 weeks of treatment, risperidone has no significant effect on P300, however risperidone reduces P200 amplitude. This latter effect of risperidone on neural resources responsible for P200 generation could be partly explained through the action of dopamine. Subsequently, we used simultaneous EEG/MEG to investigate the effects of memantine (Study III) and methylphenidate (Study IV) in healthy subjects. We found that memantine modulates MMN response without changing other ERP components. This could be interpreted as being due to the possible influence of memantine through the NMDA receptors on auditory change- detection mechanism, with processing of auditory stimuli remaining otherwise unchanged. Further, we found that methylphenidate does not modulate the MMN response. This finding could indicate no association between catecholaminergic activities and electrophysiological measures of preattentive auditory discrimination processes reflected in the MMN. However, methylphenidate decreases the P200 amplitudes. This could be interpreted as a modulation of auditory information processing reflected in P200 by dopaminergic and noradrenergic systems. Taken together, our set of studies indicates a complex pattern of neurochemical influences produced by the antipsychotic drugs in the neural substrate of auditory information processing in patients with schizophrenia spectrum disorders and by the pharmacological challenges in healthy subjects studied with ERPs and ERFs.

Lithium for schizophrenia revisited: A systematic review and meta-analysis of randomized controlled trials

Background: Clinicians frequently use lithium to augment antipsychotic medication in schizophrenia. Therefore, we undertook a systematic review and meta-analysis of the use of lithium in the treatment of schizophrenia. Data sources and study selection: Randomized controlled trials examining lithium (as a sole or an adjunctive compound) in participants with schizophrenia or related disorders were searched in the register of the Cochrane Schizophrenia Group. No language restrictions were applied. The Boolean phrase [lithium* or lithicarb or eskalith or lithobid or lithane or cibalith-s or quilonum or hypnorex] was used to locate articles. The search strategy initially identified 90 references. The authors of the included studies were contacted to obtain original patient data. The data were combined in a meta-analysis. The main outcome parameters were the number of patients with a clinically significant response and the number of patients leaving the studies early. Results: The meta-analysis includes 20 studies (N = 611). The evidence shows that lithium as a sole agent is ineffective in the treatment of schizophrenia. Eleven trials examined the augmentation of antipsychotics with lithium. More patients who received lithium augmentation than those who received antipsychotics alone were classified as responders. However, the superiority was not consistent across different response thresholds, and when patients with prominent affective symptoms were excluded from the analysis, the advantage of lithium augmentation was not significant (p = .07). Significantly more patients taking lithium left the trials early, suggesting a lower acceptability of lithium augmentation compared with that of taking antipsychotics alone. Conclusion: Despite some evidence in favor of lithium augmentation, the overall results are inconclusive. A large trial of lithium augmentation of antipsychotic medications will be required in order to detect a benefit of small effect size in patients with schizophrenia who lack affective symptoms.

Practice Links [Issue 53, June 2013]

Practice Links is a free e-publication for practitioners working in Irish social services, voluntary and nongovernmental sectors. Practice Links was created to enable practitioners to keep up-to-date with new publications, electronic resources and conference opportunities. Issue 53 includes reviews of research on medication for schizophrenia and the impact of housing improvements on health.

Effect of subjective reasoning and neurocognition on medication adherence for persons with schizophrenia

Objective: This study investigated the relationship between patients' reasoning about medication adherence and neurocognitive and clinical indices for a treatment-compliant sample of Japanese patients with schizophrenia.

Methods: Subjective reasoning about medication adherence was assessed by the Rating of Medication Influences (ROMI) scale. General intelligence, executive function, and verbal memory were assessed by the Wechsler Adult Intelligence Scale-Revised, Wisconsin Card Sorting Test, and Rey Auditory Verbal Learning Test, respectively.

Results: Higher prevention scores were associated with lower executive functioning and older age. Influence of others was associated with years of education, medication dosage, and IQ, and medication affinity was associated with education.

Conclusions: These results suggest that executive functioning, education, and general IQ may all be important factors in individual motivation for medication adherence.

Schizophrenia, psychotropic medication, and cataract

OBJECTIVE: To compare the distribution of cataract types between psychiatric patients diagnosed with schizophrenia and the general population not exposed to psychotropic medication, and to compare cataract prevalence between users and nonusers of various psychotropic medications in the general community. DESIGN: Case-control. PARTICIPANTS: A total of 151 (93%) eligible patients from a community mental health service and 3271 (83%) eligible residents from the Melbourne Visual Impairment Project (VIP) were examined. MAIN OUTCOME MEASURES: All patients 40 years of age and older from a community mental health service and residents of nine randomly selected areas of Melbourne were eligible. Best-corrected distance visual acuity was determined using a 4-m logarithm of the minimum angle of resolution (LogMAR) chart. The presence of cataract was determined by photographs or slit-lamp examination using direct and indirect retroillumination. Anterior, cortical, nuclear, and posterior subcapsular cataracts were measured. Participants from the Melbourne VIP were classified as to whether they had taken benzodiazepams, phenothiazines, thioxanthenes, butyrophenols, tricyclic antidepressants, or monoamine oxidase inhibitors for at least 12 months during their lifetime. RESULTS: The distribution of cataract type varied between persons with and without schizophrenia. Anterior subcapsular (ASC) cataract was significantly more prevalent (26%) in participants with schizophrenia from the community mental health service than Melbourne VIP participants (0.2%) not exposed to psychotropic medication (chi-square, 1 degree of freedom = 605.5, P = 0.001). This remained significant after controlling for age (odds ratios = 250, 95% confidence interval = 83.3, 1000). The distribution of the age-related cataract was similar across all groups of psychotropic medication users with the exception of the phenothiazine users. They had less of all types of the age-related cataracts, despite being slightly older than the control group (mean age, 60.0 vs. 58.4, t test = 0.85, P = 0.40). However, only cortical cataract in the phenothiazine group was statistically lower (chi-square, 1 degree of freedom = 3.96, P = 0.047). CONCLUSION: This study has identified the need to investigate whether other newer agents, especially high-potency medications, cause ASC opacities if a certain threshold of exposure to psychotropic medications must be attained to develop cataract, or if schizophrenia itself is associated with cataract formation.

EEG microstate duration and syntax in acute, medication-naive, first-episode schizophrenia: a multi-center study

In young, first-episode, productive, medication-naive patients with schizophrenia, EEG microstates (building blocks of mentation) tend to be shortened. Koenig et al. [Koenig, T., Lehmann, D., Merlo, M., Kochi, K., Hell, D., Koukkou, M., 1999. A deviant EEG brain microstate in acute, neuroleptic-naïve schizophrenics at rest. European Archives of Psychiatry and Clinical Neuroscience 249, 205–211] suggested that shortening concerned specific microstate classes. Sequence rules (microstate concatenations, syntax) conceivably might also be affected. In 27 patients of the above type and 27 controls, from three centers, multichannel resting EEG was analyzed into microstates using k-means clustering of momentary potential topographies into four microstate classes (A–D). In patients, microstates were shortened in classes B and D (from 80 to 70 ms and from 94 to 82 ms, respectively), occurred more frequently in classes A and C, and covered more time in A and less in B. Topography differed only in class B where LORETA tomography predominantly showed stronger left and anterior activity in patients. Microstate concatenation (syntax) generally were disturbed in patients; specifically, the class sequence A→C→D→A predominated in controls, but was reversed in patients (A→D→C→A). In schizophrenia, information processing in certain classes of mental operations might deviate because of precocious termination. The intermittent occurrence might account for Bleuler's “double bookkeeping.” The disturbed microstate syntax opens a novel physiological comparison of mental operations between patients and controls.

Smoking and schizophrenia: is symptom profile related to smoking and which antipsychotic medication is of benefit in reducing cigarette use?

Smoking rate is disproportionately high among patients with schizophrenia, resulting in significant morbidity and mortality. However, cigarette smoking has been reported to have beneficial effects on negative symptoms, extrapyramidal symptoms, cognitive functioning and mood symptoms. Therefore, smoking cessation may worsen disability in schizophrenia. The association between smoking and these key clinical parameters was examined. Additionally, severity of smoking across four different antipsychotic treatment groups was explored. One hundred and forty-six patients with schizophrenia were assessed for smoking using expired carbon monoxide and smoking history. They were administered the Positive and Negative Symptom Scale, The Extrapyramidal Symptom Rating Scale, the Barnes Akathisia Rating Scale, Reitans Trail-making Test (A and B) and General Health Questionnaire-28. There was no difference in the chlorpromazine equivalent dose of any of the medications studied. Atypical agents were associated with significantly lower levels of smoking when compared with typical medications. There was no difference in smoking severity between the individual atypical medications examined. Similarly, there were no significant differences between smoking and non-smoking groups with regard to Positive and Negative Symptom Scale, Extrapyramidal Symptom Rating Scale, Trail-making Test and General Health Questionnaire-28. However, there was a significant difference between these groups with the smoking group demonstrating less akathisia. Smoking is not associated with positive, negative cognitive and mood symptoms in schizophrenia. Smoking is associated with lower levels of antipsychotic induced akathisia. Clinicians should not be discouraged from helping patients stop smoking for fear of worsening symptoms. However, akathisia may emerge upon cessation of smoking. Switching patients from typical to atypical antipsychotics may assist patients with schizophrenia to give up smoking.

An intervention for substance abuse in schizophrenia

Describes a cognitive-behavioral intervention for alcohol and cannabis abuse with schizophrenic patients. The intervention integrates substance abuse treatment with other aspects of psychosis management, including assessment, use of anti-psychotic medication, and training in coping skills.

A DRD2 polymorphism predicts PANSS score variability in schizophrenia patients treated with antipsychotics

Antipsychotic medications act as either antagonists or partial agonists of the dopamine D2 receptor (DRD2) and antipsychotic drugs vary widely in their binding affinity for the D2 receptor (Kapur and Seeman, 2000). The DRD2 957CNT (rs6277) polymorphism has previously been associated with schizophrenia (Lawford et al., 2005) and the T-allele of the 957CNT polymorphism is associated with reduced mRNA stability and synthesis of the dopamine D2 receptor (Duan et al., 2003). The aim of the study was to determine if the rs6277 polymorphism predicts some of the variability of positive and negative symptoms observed in schizophrenia patients being treated with antipsychotic medication.

Caregiving attachment in mothers with schizophrenia: Child and Youth Mental Health Service, Mater Misericordiae Health Services, South Brisbane, Australia

The assessment of parenting capacity and appropriate provision of services to assist parents with mental illness requires improved understanding of how a mental illness may affect the parent-child relationship. Mothers with mental illness may be defensive when providing self-report accounts of their parenting. Within the framework of attachment theory, this study developed a methodology for investigating the quality and characteristics of caregiving through exploration of the mothers' perceptions and strategies in managing her child at bedtime. Utilising questions derived from caregiving attachment research, five mothers with schizophrenia participated in a semi-structured interview concerning bedtime separation. In addition the mothers completed a modified standardised measure of attachment style, the Parent Bonding Instrument, to provide information regarding how they perceived their parenting style. The mothers demonstrated very poor understanding of their child's bedtime anxiety. They described difficulty being effective with bedtime strategies and attributed it to medication-induced fatigue. The interview data contrasted significantly with the Parent Bonding Instrument data in which the mothers did not identify concerns in themselves as caregivers. This study demonstrated the feasibility of a novel approach to gathering information regarding parenting from mothers with a diagnosis of schizophrenia.

A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset : HapMap tag-single-nucleotide polymorphism analysis

Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain which is known to be important in the aetiology of schizophrenia. It is therefore not surprising that most antipsychotic medication acts on the Dopamine D2 receptor. DRD2 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. Methods: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single nucleotide polymorphisms (SNPs) in DRD2 using a multiplex mass spectrometry method. SNPs were chosen using a haplotype block-based gene-tagging approach so the entire DRD2 gene was represented. Results: One polymorphism rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared to controls. Conclusions: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor age of onset.

Patterns of service use among persons with Schizophrenia and other psychotic disorders

Objective: This study assessed 12-month service use patterns among people with psychotic disorders and sought to identify determinants of service use. Methods: As part of a large two-phase Australian study of psychotic disorders, structured interviews were conducted with a stratified random sample of adults who screened positive for psychosis. Demographic characteristics, social functioning, symptoms, mental health diagnoses, and use of psychiatric and nonpsychiatric services were assessed. Data were analyzed for 858 persons who had an ICD-10 diagnosis of a psychotic disorder and who had been hospitalized for less than six months during the previous year. Results: People with psychotic disorders had high levels of use of health services, both in absolute terms and relative to people with nonpsychotic disorders. Those with psychotic disorders were estimated to have an average of one contact with health services per week. Use of psychiatric inpatient services was associated with parenthood, higher symptom levels, recent attempts at suicide or self-harm, personal disability, medication status, and frequency of alcohol consumption. Services provided by general practitioners (family physicians) were more likely to be obtained by older people, women, people with greater availability of friends, those with fewer negative symptoms, and those whose service needs were unmet by other sources. People who were high users of health services also reported having more contact with a range of non-health agencies. Conclusions: The predictors of service use accounted for small proportions of the variance in overall use of health services. The role of general practitioners in providing and monitoring treatment programs and other psychosocial interventions needs to be acknowledged and enhanced.