The Microbiome: A New Target for Research and Treatment of Schizophrenia and its Resistant Presentations? A Systematic Literature Search and Review.

Background: The gastrointestinal system hosts roughly 1,800 distinct phyla and about 40,000 bacterial classes, which are known as microbiota, and which are able to influence the brain. For instance, microbiota can also influence the immune response through the activation of the immune system or through the release of mediators that are able to cross the brain blood barrier or that can interact with other substances that have free access to the brain, such as tryptophan and kynurenic acid, which is a metabolite of tryptophan and which has been involved in the pathogenesis of schizophrenia. Objectives: This paper reviews the possible relationships between microbiome, schizophrenia and treatment resistance. Given the possibility of a role of immune activation and alterations, we also describe the relationship between schizophrenia and immune inflammatory response. Finally, we report on the studies about the use of probiotic and prebiotics in schizophrenia. Methods: Cochrane library and PubMed were searched from the year 2000 to 2018 for publications about microbiome, immune-mediated pathology, schizophrenia and neurodevelopmental disorders. The following search string was used: (microbiome or immune mediated) AND (schizophrenia OR neurodevelopmental disorder). Associated publications were hand-searched from the list of references of the identified papers. A narrative review was also conducted about the use of probiotics and prebiotics in schizophrenia. Results: There exists a close relationship between the central nervous system and the gastrointestinal tract, which makes it likely that there is a relationship between schizophrenia, including its resistant forms, and microbiota. This paper provides a summary of the most important studies that we identified on the topic. Conclusions: Schizophrenia in particular, remain a challenge for researchers and practitioners and the possibility of a role of the microbiome and of immune-mediated pathology should be better explored, not only in animal models but also in clinical trials of agents that are able to alter gut microbiota and possibly influence the mechanisms of gastrointestinal inflammation. Microbiome targeted treatments have not been well-studied yet in patients with mental illness in general, and with schizophrenia in particular. Nonetheless, the field is well worth of being appropriately investigated.

Deep Brain Stimulation of the Anterior Limb of the Internal Capsule May Be Efficacious for Explosive Aggressive Behaviour.

BACKGROUND: Intermittent explosive disease (IED) is a psychiatric disorder characterized by intermittent attacks of rage and violence frequently resistant to pharmacological therapy. Deep brain stimulation (DBS) of the posteromedial hypothalamus has been applied with fair results and clinical improvement with some surgical morbidity due to neurovegetative side effects. The anterior limb of the internal capsule/ventral capsule/ventral striatum (VC/VS) has never been used alone as a target for this disease. OBJECTIVES: The aim of this study is to evaluate the efficacy of bilateral DBS of the VC/VS for the treatment of IED. METHODS: We performed bilateral DBS of the VC/VS in a 21-year-old patient with IED. This young man had a traumatic birth complicated by hypoxia, and he showed a mild mental impairment. Different pharmacological treatments were carried out with no results before DBS was proposed to the patient's relatives after multidisciplinary approval. RESULTS: After 22 months of high-frequency monopolar bilateral DBS of the VC/VS, the patient showed a significant improvement. Postoperative 18F-FDG PET-CT studies ruled out a reduction of the hypermetabolic areas located in the limbic system previously detected in pre-operative investigations. CONCLUSIONS: Bilateral DBS of the VC/VS may be considered for the treatment of IED without the risk of neurovegetative side effects.

Evidence of diffuse damage in frontal and occipital cortex in the brain of patients with post-traumatic stress disorder.

A number of MRI studies have shown focal or diffuse cortical gray matter (GM) abnormalities in patients with post-traumatic stress disorder (PTSD). However, the results of these studies are unclear regarding the cortical regions involved in this condition, perhaps due to the heterogeneity of the PTSD population included or to the differences in the methodology used for the quantification of the brain structures. In this study, we assessed differences in cortical GM volumes between a selected group of 25 drug-naive PTSD patients with history of adulthood trauma and 25 matched non-traumatized controls. Analyses were performed by using two different automated methods: the structural image evaluation using normalization of atrophy (SIENAX) and the voxel-based morphometry (VBM), as we trusted that if these complementary techniques provided similar results, it would increase the confidence in the validity of the assessment. Results of SIENAX and VBM analyses similarly showed that cortical GM volume decreases in PTSD patients when compared to healthy controls, particularly in the frontal and occipital lobes. These decreases seem to correlate with clinical measures. Our findings suggest that in drug-naïve PTSD patients with a history of adulthood trauma, brain structural damage is diffuse, with a particular prevalence for the frontal and occipital lobes, and is clinically relevant.

Magnetic resonance imaging volumes of the hippocampus in drug-naïve patients with post-traumatic stress disorder without comorbidity conditions.

Most brain imaging studies have showed smaller hippocampal volume in adults with chronic PTSD; however, some other studies have not replicated this finding. Most of these investigations included subjects with other psychiatric comorbidities, such as major depression or alcohol abuse. The prevalence of psychiatric comorbidities in PTSD is generally high and this makes it difficult, if not impossible, to disentangle the contribution of other disorders to hippocampal volume. Therefore, the main goal of the current study is to compare hippocampal volumes of healthy subjects and drug-naïve patients with PTSD caused by different types of mixed civilian traumas (i.e. car accident, physical abuse, sudden death of a family member, assault or robbery, natural disaster and traumatic abortion) and without comorbidity conditions. Magnetic resonance imaging (MRI) was used to measure the hippocampi, total cerebrum, gray matter, white matter and cerebrospinal fluid volumes in 34 patients with single diagnosis of PTSD, and 34 case-matched non-PTSD comparison subjects. The patients with single diagnosis of PTSD had an 11.8% smaller left hippocampus (p<0.001) and an 8.7% smaller right hippocampus (p=0.003) than the healthy controls. The results were controlled for the total brain volume and for gray matter volumes. Subjects with PTSD also displayed lower overall gray matter volume (p=0.006). There were no significant correlations between hippocampal volumes and illness duration or severity of PTSD. The findings indicate the presence of smaller hippocampal volumes in drug-naïve patients with single diagnosis of PTSD, compared with healthy subjects.

Repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of panic disorder (PD) with comorbid major depression.

BACKGROUND: Studies suggest that the dorsolateral prefrontal cortex (DLPFC) participates in neural circuitry that is dysregulated in Panic Disorder (PD) and Major Depressive Disorder (MDD). We tested whether low-frequency repetitive Transcranial Magnetic Stimulation (rTMS) could normalize the overactivity of right frontal regions and thereby improve symptoms. METHODS: Six patients with PD and comorbid MDD were treated with daily active 1-Hz rTMS to the right DLPFC for 2 weeks in this open-label trial. RESULTS: Clinical improvements were apparent as early as the first week of treatment. After the second week, 5/6 of patients showed improvements in panic and anxiety, and 4/6 showed a decrease in depression, with sustained improvement at 6 months of follow-up. Right hemisphere resting motor threshold increased significantly after rTMS. LIMITATIONS: Limitations of this study are the open design and the small sample size. CONCLUSIONS: Slow rTMS to the right DLPFC resulted in significant clinical improvement and reduction of ipsilateral motor cortex excitability. Replications in larger sample will help to clarify the relevance of this preliminary data and to define the potential role of right DLPFC rTMS in panic with major depression.

Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS).

There is evidence that motor and premotor cortex are hyperexcitable in obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). We tested whether low-frequency repetitive transcranial magnetic stimulation (rTMS) could normalize overactive motor cortical regions and thereby improve symptoms. Subjects with OCD or TS were treated with active rTMS to the supplementary motor area (SMA) for 10 daily sessions at 1 Hz, 100% of motor threshold, 1200 stimuli/day. Suggestions of clinical improvement were apparent as early as the first week of rTMS. At the second week of treatment, statistically significant reductions were seen in the YBOCS, YGTSS, CGI, HARS, HDRS, SAD, BDI, SCL-90, and SASS. Symptoms improvement was correlated with a significant increase of the right resting motor threshold and was stable at 3 months follow-up. Slow rTMS to SMA resulted in a significant clinical improvement and a normalization of the right hemisphere hyperexcitability, thereby restoring hemispheric symmetry in motor threshold.

Attachment and panic disorder.

A dysfunctional relationship between parents and children can influence cognitive and emotional development and contribute to the development of psychiatric disorders, particularly panic disorder (PD). With the aim of exploring childhood experiences of parenting in PD patients, we compared subjectively perceived climate and objective recall by administering the Parental Bonding Instrument and 10 adjunctive items to 22 out-patients and 22 matched controls. Our analysis showed that DSM-III-R-diagnosed PD patients reported their parents to be significantly less caring than did the control group, while there was no significant difference in objective recall of parenting experiences.