A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder

Aberrant glutamate neurotransmission has been implicated in the pathophysiology of bipolar disorder with accumulating evidence from imaging, post-mortem and pathology studies. Studies investigating in vivo changes to the glutamatergic system have not been as consistent and warrant clarification. Studies utilizing proton-magnetic resonance spectroscopy (¹H-MRS) have reported increased levels of combined glutamate and glutamine (“Glx”), which have been linked to impairments in N-methyl-d-aspartate (NMDA) receptor function. Similarly, neurophysiological studies utilising mismatch negativity (MMN) as an index of NMDA receptor function, have reported impairments in bipolar disorder. Here, we provide a systematic review of the literature in regards to the concentration of Glx and the magnitude of MMN in bipolar disorder. Separate meta-analyses revealed that bipolar disorder was associated with increased Glx concentration and decreased MMN—both measured frontally. The current findings corroborate previous evidence indicating that bipolar disorder is characterized by a perturbed frontal glutamate system. These observed changes in bipolar disorder might manifest as impairments in neuronal–glial interactions that lead to disrupted neuronal output and ultimately result in the characteristic neurocognitive sequelae associated with this disorder.     

Preliminary evidence for medication effects on functional abnormalities in the amygdala and anterior cingulate in bipolar disorder

Rationale Abnormal amygdala and frontocortical responses to emotional stimuli are implicated in bipolar disorder (BD) and have been proposed as potential treatment targets.Objectives The aim of this study was to investigate amygdala and frontocortical responses to emotional face stimuli in BD and the influences of mood-stabilizing medications on these responses.Methods Functional magnetic resonance imaging was performed while 17 BD participants (5 unmedicated) and 17 healthy comparison (HC) participants viewed faces with happy, sad, fearful, or neutral expressions.Results The group by stimulus-condition interaction was significant (p<0.01) for amygdala activation, with the greatest effects in the happy face condition. Relative to HC, amygdala increases were greater in unmedicated BD, but lower in medicated BD. Rostral anterior cingulate (rAC) activation was decreased in unmedicated BD compared to HC; however, BD participants taking medication demonstrated rAC activation similar to HC participants.Conclusions Although the sample sizes were small, these preliminary results suggest that BD is associated with increased amygdala and decreased rAC response to emotional faces. The findings also provide preliminary evidence that mood-stabilizing medications may reverse abnormalities in BD in the response of an amygdala–frontal neural system to emotional stimuli.     

A 1HMRS study of the anterior cingulate gyrus in euthymic bipolar patients

INTRODUCTION: The anterior cingulate region has been implicated in the pathophysiology of mood disorders. Studies have reported anatomical and functional abnormalities in this region in bipolar disorder patients. Few neurochemical studies have evaluated this region, especially on medicated bipolar patients. Lithium has been reported to increase NAA levels but not by all studies. We used proton magnetic spectroscopy ((1)HMRS) to measure the levels of N-acetyl-L-aspartate (NAA) and choline (Cho) relative to creatine (Cr) in the anterior cingulate of euthymic medicated bipolar subjects. METHODS: (1)HMRS was performed using a GE Signa 1.5 Tesla scanner in 13 euthymic bipolar patients who were taking lithium for at least four weeks before the scan and in 15 normal controls. The (1)HMRS signal was collected from an 8 cm(3) voxel placed in the anterior cingulate. Data analysis was performed with the automated PROBE/SV quantification tool. RESULTS: NAA/Cr and Cho/Cr ratios were not significantly different between patients and controls (NAA/Cr: 1.60 +/- 0.34 in patients, 1.68 +/- 0.34 in controls; Cho/Cr: 1.13 +/- 0.13 in patients, 1.11 +/- 0.20 in controls). CONCLUSIONS: We did not find a significant difference in the NAA/Cr and Cho/Cr ratio between bipolar patients and healthy controls. Chronic administration of psychotropic drugs could have had an effect on NAA/Cr levels of bipolar patients.     

Importance of open access to atypical antipsychotics for the treatment of schizophrenia and bipolar disorder: a European perspective

ABSTRACT

Objective: To assess European psychiatrists' prescribing behaviour and their perceived need for access to a wide range of atypical antipsychotics for patients with schizophrenia and bipolar disorder.

Methods: A blinded, internet survey of psychiatrists from the UK, Germany, Italy and the Netherlands occurred in 2007. Key inclusion criteria for psychiatrists: practising full time; practising for 5–35 years; prescribed atypical antipsychotics in prior 6 months to ≥20 patients with schizophrenia or bipolar disorder. Eligible psychiatrists selected records for four patients with schizophrenia or bipolar disorder for whom they prescribed ≥1 atypical antipsychotic since January 2004.

Results: Survey response rates were: UK, 14.8% (n?=?107); Germany, 9.6% (n?=?104); Italy, 8.9% (n?=?101) and the Netherlands, 3.7% (n?=?51); 363 psychiatrists reported on 1442 patients. Psychiatrists perceived a greater difference among atypical antipsychotics as a class (mean, 5.1 on a 7-point scale [7 = ‘highly differentiated’]) but not selective serotonin reuptake inhibitors (mean, 3.6). On average, psychiatrists used 6.8 different atypical antipsychotics across their patients with schizophrenia and 4.4 across their patients with bipolar disorder, with 2.5 and 2.4 changes required following first-line treatment to stabilise therapy, respectively. The most common reason for switching medication was lack of efficacy. Psychiatrists reported that expected consequences for patients should access to atypical antipsychotics be restricted would include illness deterioration, non-adherence and hospitalisation.

Conclusions: Although this study is limited by potential selection biases, these data suggest that European psychiatrists tailor antipsychotic medications for patients with schizophrenia or bipolar disorder according to patients' needs and specific drug attributes.     

A proton magnetic resonance spectroscopy investigation of the dorsolateral prefrontal cortex in acute mania

BACKGROUND: Several neurochemical abnormalities have been reported in bipolar disorder (BD), but the exact mechanisms that underlie its pathophysiology remain to be elucidated. Proton magnetic resonance spectroscopy (1HMRS) allows in vivo measurements of certain neurometabolites in the human brain. 1HMRS was used to investigate the dorsolateral prefrontal cortex (DLPFC) in bipolar subjects during a manic or mixed phase. N-acetyl-L-aspartate (NAA), choline-containing molecules (Cho), creatine plus phosphocreatine (Cr) and myoinositol (Ino) were measured. METHOD: Ten bipolar patients (nine manic, one mixed), diagnosed by a semi-structured clinical interview (SCID), and ten age- and gender-matched healthy volunteers were studied. Absolute neurometabolites levels were measured from two 8 cm3 voxels placed in left and right DLPFC using a short TE 1HMRS method at 1.5 T. T1- and T2-weighted anatomical magnetic resonance imaging was performed to exclude any neuroanatomical abnormality. RESULTS: No significant differences were found for NAA, Cho, Cr, Ino, NAA/Cr, Cho/Cr or Ino/Cr between patients and controls. Manic/mixed patients had significantly higher left-to-right myoinositol ratios in DLPFC (p = 0.044). CONCLUSIONS: Increased left-to-right myoinositol ratios in the DLPFC in bipolar patients during acute mania may represent a dysfunction in the phosphoinositide-signaling pathway. Longitudinal studies with larger samples of unmedicated patients assessing pre- and post-treatment times will be required for further clarification of the time course of these abnormalities and the relationship with treatment effects.     

Neurological soft signs in bipolar disorder in comparison to healthy controls and schizophrenia: A meta-analysis

Neurological soft signs (NSS) are subtle deficits in motor coordination, sensory integration, and sequencing of complex motor acts. Increased NSS is a well-established feature of patients with schizophrenia but a relatively smaller number of studies have investigated NSS in bipolar disorder (BD). Some authors but not others suggested that NSS can distinguish schizophrenia from BD. We conducted a meta-analysis of 18 studies to quantitatively review NSS in BD in comparison to schizophrenia and healthy controls. The current meta-analysis compared NSS scores of 725 BD patients and 634 healthy controls, and 391 BD and 471 schizophrenia patients. Patients with BD had significantly higher NSS scores (d?=?1.14, CI?=?0.89–1.44) than healthy controls and increased scores in BD was evident in all aspects of NSS (d?=?0.88–0.99). BD was associated with a less severe increase in NSS compared to schizophrenia, however, between-group difference was modest (d?=?0.42, CI?=?0.18–0.65). The results of this meta-analysis demonstrated that BD is characterized by a robust increase in NSS which is only moderately less severe than schizophrenia. Increased NSS is a common feature of both disorders.     

H magnetic resonance spectroscopy investigation of the anterior cingulate cortex and prefrontal cortex in chronic pain patients]

We investigated the absolute concentration of N-acetylaspartate (NAA) in the anterior cingulated cortex (ACC), and prefrontal cortex (PFC) in chronic pain patients by proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS was performed with a 1.5T MR system on a voxel in the thalamus, ACC, and PFC bilaterally, in 48 chronic pain patients and 23 normal control subjects. We measured the absolute concentration of NAA using an LC-Model. There were 12 patients whose NAA concentration in the ACC or PFC was significantly, lower than the mean NAA concentration of the normal control subjects. Ten of these 12 patients needed a psychological approach. 1H-MRS suggests that NAA concentration in the ACC or PFC is associated with the necessity of a psychological approach. 1H-MRS may serve as a useful non-invasive tool for evaluating neural activity of the thalamus, anterior cingulated cortex, and prefrontal cortex in chronic pain patients.     

Functional magnetic resonance imaging of a parametric working memory task in schizophrenia: relationship with performance and effects of antipsychotic treatment

Rationale  

Working memory dysfunction is frequently observed in schizophrenia. The neural mechanisms underlying this dysfunction remain unclear, with functional neuroimaging studies reporting increased, decreased or unchanged activation compared to controls.     

PLACID study: A randomized trial comparing the efficacy and safety of inhaled loxapine versus intramuscular aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder

The aim of the study was to investigate the efficacy and safety of inhaled loxapine compared with the intramuscular (IM) antipsychotic aripiprazole in acutely agitated patients with schizophrenia or bipolar I disorder. PLACID was an assessor-blind, parallel-group trial conducted in 23 centres in the Czech Republic, Germany, Spain, and Russia. Patients (aged 18–65 years) diagnosed with schizophrenia or bipolar I disorder experiencing acute agitation (Clinical Global Impression [CGI]-Severity score ≥ 4) while hospitalized or attending an emergency room were randomized to receive up to two doses of inhaled loxapine 9.1?mg or IM aripiprazole 9.75?mg (≥ 2?h between doses) during the 24-h study period. The primary efficacy endpoint was time to response (CGI-Improvement score 1 [very much improved] or 2 [much improved]). The primary analysis included randomized patients who provided informed consent (full analysis set [FAS]); the safety analysis included all patients who received study medication. The FAS comprised 357 patients (enrolled December 2, 2014 – October 31, 2016). The between-treatment difference in median time to CGI-Improvement response was 10?min (95% CI 0.0–30.0); p = 0.0005) in favour of inhaled loxapine (median [95% CI]: 50?min [30.0–50.0] vs 60?min [50.0–90.0] with IM aripiprazole); the difference was significant at 10?min (responders: 14% [loxapine] vs 4% [aripiprazole]; p = 0.001). There were no safety issues. Inhaled loxapine reduced agitation faster than IM aripiprazole, supporting its use as a first-line option for managing acute agitation in patients with schizophrenia or bipolar disorder.     

Clozapine use in patients with schizophrenia and a comorbid substance use disorder: A systematic review

Lifetime prevalence of substance use disorders (SUD) in patients with schizophrenia is nearly 50%. Nicotine, alcohol, and cannabis are the substances most frequently used, with a high percentage of poly-substance users. There are few available data about pharmacological approaches in this population. Amongst antipsychotics, clozapine shows positive evidence in the literature. The aim of the present article is to provide systematic review on the efficacy of clozapine in SUD improvement in schizophrenic patients. PRISMA recommendations were followed (PROSPERO id: CRD42017059299). Five studies for nicotine use and nine studies for SUD (other than nicotine) were analyzed. Regarding nicotine use, results from randomized controlled trials (RCT) have found a decrease in nicotine use after 12 weeks of 200–600 mg/day clozapine, as compared with lower doses. In SUD improvement (other than nicotine), RCT have shown superiority of clozapine when compared with risperidone, in short-term studies (from 4 to 12 weeks) performed in cannabis users. In long-term studies (1 year), clozapine was equal to ziprasidone in reducing cannabis use and equal to treatment as usual in reducing alcohol use. We conclude that positive results on nicotine use are scarce and derived from studies with a low degree of evidence. Evidence of clozapine on SUD (other than nicotine) is stronger, especially when clozapine is compared with first generation antipsychotics in poly-substance users. When compared with second generation antipsychotics, clozapine was superior to risperidone but equal to olanzapine or ziprasidone in poly-substance and cannabis users.     

Longer-term treatment of patients with bipolar disorder: a 9-month observational study in Central and Eastern Europe,the Middle East and Africa

ABSTRACT

Objective: To compare the longer-term outcomes of pharmacological treatment of patients with a diagnosis of bipolar affective disorder currently suffering a manic or hypomanic episode prescribed olanzapine or non-olanzapine medication in naturalistic, clinical practice settings in Bosnia-Herzegovina, Slovakia, Slovenia, Turkey, Saudi Arabia and Egypt.

Research design and methods: Prospective, observational, non-interventional study conducted over 9 months. Inpatients or outpatients who initiated or changed oral bipolar mania medication were grouped into (1) those prescribed olanzapine at baseline (n?=?569) and (2) those not prescribed olanzapine (n?=?325).

Main outcome measure(s): The change from baseline in the Clinical Global Impression Severity scale for bipolar disorder (CGI-BP-S), the rates of symptomatic response and remission (based on CGI-BP-S) and the frequency and nature of treatment-emergent adverse events. Analyses included (1) linear or logistic regression, with adjustment for confounders, based on the last observation carried forward and (2) weighted repeated measures models that adjusted for treatment switching and patient drop-out.

Results: When results were adjusted for treatment switching and patient drop-out, patients prescribed olanzapine had significantly better CGI-BP-S scores (mean difference?=??0.24; 95% confidence interval [CI] ?0.33, ?0.16; p?<?0.001) and significantly greater odds of treatment response (odds ratio [OR] =?1.86; 95% CI 1.31, 2.65; p?<?0.001) and symptom remission (OR?=?1.65; 95% CI 1.18–2.32; p?=?0.003) than those not prescribed olanzapine. The frequency of most adverse events decreased in both groups. Patients prescribed olanzapine had significantly greater weight gain from baseline (mean increase?=?2.66?kg; 95% CI 2.35, 2.98) compared with those not prescribed olanzapine (mean increase?=?1.85?kg; 95% CI 1.51, 2.19; p?<?0.001).

Conclusions: Inclusion of olanzapine is of benefit for pharmacological treatment of patients with bipolar disorder. However, the favourable outcomes observed cannot be directly attributed to olanzapine alone because of the high prevalence of polypharmacy in the patient population.     

Screening for bipolar disorders in patients with alcohol or substance use disorders: performance of the mood disorder questionnaire

Background

Screening properties of the Mood Disorder Questionnaire (MDQ) to detect bipolar disorder (BD) in patients with substance use disorders are unknown.

Methods

403 treatment seeking patients with a substance use disorder completed the MDQ and subsequently 111 MDQ positives and 59 MDQ negatives were assessed with the Structured Clinical Interview for DSM-IV to diagnose BD. In addition, given the overlap with BD symptoms, the presence of borderline personality disorder (BPD), antisocial personality disorder (APD) and attention deficit/hyperactivity disorder (ADHD), were assessed using the Diagnostic Interview Schedule and the Structured Interview for DSM-IV Personality.

Results

Of the 170 patients with a SCID interview, 35 patients (20.6%) met criteria for a lifetime diagnosis of BD. Twenty-three patients (62.8%) with BD had a positive MDQ score and 47 of the 135 patients (34.8%) without BD had a negative MDQ score resulting in a weighted sensitivity of .43, a weighted specificity of .57, a positive predictive value of .21, a negative predictive value (NPV) of .80 and an area under the curve of .50. The area under the curve of the MDQ to detect BPD, APD, ADHD and any externalizing disorder ranged from .55 (APD) to .63 (ADHD).

Conclusions

The MDQ is not a suitable screening instrument for the detection of BD or other externalizing disorders but it could be used for ruling out the presence of BD in treatment seeking substance use disorder patients.     

Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study

Rationale The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients. Objectives To our knowledge, no longitudinal volumetric study has been performed in patients with BD, which would allow for an examination of whether lithium therapy used to treat BD can exert a long-term effect on hippocampal volume. Materials and methods We examined the effects of lithium on hippocampal volumes and recollective memory performance over a period of 2 to 4 years in 12 patients with BD who had never received pharmacotherapy before lithium initiation. Results We found bilateral increases in volume of the hippocampus over time. We also found some evidence of improvement in verbal memory performance over the 4-year measurement period as assessed by the California Verbal Learning Test. Conclusions Consistent with preclinical literature supporting the neuroprotective effects of lithium, long-term treatment is associated with preservation of recollective memory function and increased hippocampal size in vivo.     

The PDLIM5 gene and lithium prophylaxis: An association and gene expression analysis in Sardinian patients with bipolar disorder

A number of studies support the notion that lithium interacts with the protein kinase C (PKC) pathway, an important mediator of several intracellular responses to neurotransmitter signaling. PDLIM5 (PDZ and LIM domain 5; LIM) is an adaptor protein that selectively binds the isozyme PKC(epsilon) to N-type Ca(2+) channels in neurons. We tested for an association between three single nucleotide polymorphisms (SNPs) at the PDLIM5 gene and lithium prophylaxis in a Sardinian sample comprised of 155 bipolar patients treated with lithium. In order to evaluate whether PDLIM5 expression interacts with lithium response, we carried out gene expression analysis in lymphoblastoid cells of 30 bipolar patients. No association was shown between PDLIM5 polymorphisms and lithium response. When PDLIM5 expression was evaluated, no significant differences were detected between Full Responders to lithium (total score>or=7) and other patients (total score相似文献   

Amino acid metabolic processes in the temporal lobes assessed by proton magnetic resonance spectroscopy (1H MRS) in children with Down syndrome

Down syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. The overexpression of the β-amyloid precursor protein gene, located on chromosome 21, causes an increased production of the specific amyloid. The current study is a continuation of our earlier investigations relating to the profile of metabolic changes in the frontal lobes of DS patients as assessed by proton magnetic resonance spectroscopy (¹H MRS). The aims of the study were the morphological assessment of the brain using magnetic resonance imaging (MRI) and the evaluation of metabolic disorders of the temporal lobes using ¹H MRS in DS children. The study group included 20 children with DS aged 3–15 years and treated in the Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok. The control group included healthy children (n = 20). MRI scans of the heads of DS children were performed using a 1.5 T MR scanner under standard conditions. ¹H MRS investigations were also carried out to assess metabolic changes in the temporal lobes. Metabolites, such as N-acetylaspartate (NAA), glutamate-glutamine complex (Glx), choline (Cho), myoinositol (ml) and γ-aminobutyric acid (GABA), were determined in both temporal lobes with reference to the internal marker creatine (Cr). Results were compared with the control group. We found a statistically significant decrease in NAA/Cr, Cho/Cr, ml/Cr and GABA/Cr ratios. The Glx/Cr ratio in both temporal lobes of DS patients did not differ from the control group. Our results indicate metabolic neurotransmitter disorders in the central nervous system in children with DS.     

Anterior cingulate volume predicts response to psychotherapy and functional connectivity with the inferior parietal cortex in major depressive disorder

In major depressive disorder (MDD), the anterior cingulate cortex (ACC) has been associated with clinical outcome as well as with antidepressant treatment response. Nonetheless, the association between individual differences in ACC structure and function and the response to cognitive behavioral therapy (CBT) is still unexplored. For this aim, twenty-five unmedicated patients with MDD were scanned with structural and resting state functional magnetic resonance imaging before the beginning of CBT treatment. ACC morphometry was correlated with clinical changes following psychotherapy. Furthermore, whole-brain resting state functional connectivity with the ACC was correlated with clinical measures. Greater volume in the left subgenual (subACC), the right pregenual (preACC), and the bilateral supragenual (supACC) predicted depressive symptoms improvement after CBT. Greater subACC volume was related to stronger functional connectivity with the inferior parietal cortex and dorsolateral prefrontal cortex. Stronger subACC-inferior parietal cortex connectivity correlated with greater adaptive rumination. Greater preACC volume was associated with stronger functional connectivity with the inferior parietal cortex and ventrolateral prefrontal cortex. In contrast, greater right supACC volume was related to lower functional connectivity with the inferior parietal cortex. These results suggest that ACC volume and its functional connectivity with the fronto-parietal cortex are associated with CBT response in MDD, and this may be mediated by adaptive forms of rumination. Our findings support the role of the subACC as a potential predictor for CBT response.     

The effect of 5-HTTLPR and a serotonergic multi-marker score on amygdala,prefrontal and anterior cingulate cortex reactivity and habituation in a large,healthy fMRI cohort

Major depressive disorder (MDD) is characterized by low mood for at least two weeks. Impaired emotion regulation has been suggested to be the consequence of dysfunctional serotonergic regulation of limbic and prefrontal regions, especially the amygdala, the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC). The impact of genetic variation on brain function can be investigated with intermediate phenotypes. A suggested intermediate phenotype of MDD is emotion recognition: The 5-HTTLPR polymorphism of SLC6A4 as well as other serotonergic genes have been associated with amygdala and prefrontal function during emotion recognition. Previously, it has been suggested that habituation is a more reliable index of emotion recognition than functional activation. We examined the relationship of genes involved in serotonergic signaling with amygdala as well as prefrontal functional activation and habituation during an emotion recognition task in 171 healthy subjects. While effects of 5-HTTLPR and of a serotonergic multi-marker score (5-HTTLPR, TPH1(rs1800532), TPH2(rs4570625), HTR1A(rs6295) and HTR2A(rs6311)) on amygdala activation did not withstand correction for multiple regions of interest, we observed a strong correlation of the multi-marker score and habituation in the amygdala, DLPFC, and ACC. We replicated a well-studied intermediate phenotype for association with 5-HTTLPR and provided additional evidence for polygenic involvement. Furthermore, we showed that task habituation may be influenced by genetic variation in serotonergic signaling, particularly by a serotonergic multi-marker score. We provided preliminary evidence that PFC activation is an important intermediate phenotype of MDD. Future studies are needed to corroborate the results in larger samples.