Akihito Uezato

Major depression and comorbid substance use disorders

Purpose of review The presentation of major depressive disorder is often complicated by the co-occurrence of substance use disorders, such as alcohol and illicit drug abuse or dependence. The article reviews the recent systematic research on the distinguishing baseline characteristics including demographic characteristics and the influence of family history, and clinical features such as depressive symptomatology and suicidal ideation, and the outcome of treatment for depression in patients with comorbid major depressive disorder and substance use disorders. The review also addresses the possible explanations cited in the literature as to why these two disorders tend to co-occur and the implications of the comorbidity of these illnesses on treatment. Recent findings Nearly one-third of patients with major depressive disorder also have substance use disorders, and the comorbidity yields higher risk of suicide and greater social and personal impairment as well as other psychiatric conditions. Although the treatment of comorbid major depressive disorder and substance use disorders with medication is likely effective, the differential treatment effects based on substance use disorder comorbidity have been understudied. Summary Emerging results of recent studies comparing the outcome of major depressive disorder patients with comorbid major depressive disorder and substance use disorders suggest that there are fewer differential effects based on comorbidity than previously anticipated by older assumptions from smaller, less methodologically rigorous studies.

Vesicular glutamate transporter mRNA expression in the medial temporal lobe in major depressive disorder, bipolar disorder, and schizophrenia

BACKGROUND Altered glutamate transmission has been found in the medial temporal lobe in severe psychiatric illnesses, including major depressive disorder (MDD) and bipolar disorder (BD). The vesicular glutamate transporters (VGLUTs) have a pivotal role in presynaptic release of glutamate into the synaptic cleft. We investigated this presynaptic marker in major psychiatric illness by measuring transcript expression of the VGLUTs in the medial temporal lobe. METHODS The study sample comprised four groups of 13 subjects with MDD, BD, or schizophrenia (SCZ), and a comparison group from the Stanley Foundation Neuropathology Consortium. In situ hybridization was performed to quantify messenger RNA (mRNA) expression of VGLUT 1, 2, and 3 in medial temporal lobe structures. We also examined the same areas of rats treated with antidepressants, a mood stabilizer, and antipsychotics to assess the effects of these medications on VGLUT mRNA expression. RESULTS We found decreased VGLUT1 mRNA expression in both MDD and BD in the entorhinal cortex (ERC), decreased VGLUT2 mRNA expression in MDD in the middle temporal gyrus, and increased VGLUT2 mRNA expression in SCZ in the inferior temporal gyrus (ITG). We also found a negative correlation between age and VGLUT1 mRNA expression in BD in the ERC and ITG. We did not find any changes in VGLUT mRNA expression in the hippocampus in any diagnostic group. We found decreased VGLUT1 mRNA expression in rats treated with haloperidol in the temporal cortex. CONCLUSIONS These data indicate region-specific alterations of presynaptic glutamate innervation in the medial temporal lobe in the mood disorders.

Further evidence for a male-selective genetic association of synapse-associated protein 97 (SAP97) gene with schizophrenia

BackgroundThe synapse-associated protein 97 gene (SAP97) encodes a regulatory scaffold protein for the localization of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) type glutamate receptors. We have recently demonstrated nominally significant associations between SAP97 gene and schizophrenia among Japanese males. The present study aimed to replicate these findings using an independent and larger sample.MethodsWe investigated seven SAP97 single nucleotide polymorphisms (SNPs) that displayed a significant association with schizophrenia in our preceding study in an independent Japanese population consisting of a total of 393 unrelated patients with schizophrenia (232 males and 161 females) and 393 unrelated control subjects (211 males and 182 females).ResultsThe SNP rs9843659 showed a significant genotypic association with male patients in a recessive model (p = 0.037). The analysis of the combined data from the current and prior studies also demonstrated a significant association of this SNP (p = 0.0039). The meta-analysis for the allele frequency covering the two studies yielded an odds ratio of 1.38.ConclusionsThe present study replicated the previously reported male-selective genetic association between the SAP97 polymorphism and schizophrenia. These findings further support the possible involvement of the SAP97 gene variation in the susceptibility to schizophrenia in males and in the genetic basis for sex differences in the disorder.

Changes in cortical N-methyl-d-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide

Objectives: In humans, depending on dose, blocking the N-methyl-d-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls. Method: We measured levels of NMDARs (using [3H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls. Results: Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (–17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV–VI; –19%, p < 0.01) and GRIN2C mRNA (laminae I–VI; –27%, p < 0.05) were lower in the anterior cingulate cortex and NMDAR binding was lower in the outer lamina IV of the dorsolateral prefrontal cortex (–19%, p < 0.01). In major depressive disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p < 0.05). In suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p < 0.01) but lower (–35%, p = 0.02) in dorsolateral prefrontal cortex while post-synaptic density protein 95 was higher (+26%, p < 0.05) in anterior cingulate cortex. Conclusion: These data suggest that differences in cortical NMDAR expression and post-synaptic density protein 95 are present in psychiatric disorders and suicide completion and may contribute to different responses to ketamine.

Anhidrosis associated with hypothalamic lesions related to anti-aquaporin 4 autoantibody

Serum anti-aquaporin 4 (AQP4) antibody is detected with high specificity in patients with neuromyelitis optica (NMO), characterised by recurrent optic neuritis and longitudinally extensive transverse myelitis [1, 2]. Three NMO patients with anti-AQP4 antibody were reported to have hypothalamic lesions, showing reduced hypocretin-1 levels in cerebrospinal fluid (CSF) and symptomatic narcolepsy [3]. Although the hypothalamus and hypocretin-1 regulate autonomic functions as well as sleep, autonomic functions in NMO patients with hypothalamic lesions have not been described well. Here we report the case of a patient with anhidrosis and narcolepsy as initial symptoms of disorders related to anti-AQP4 antibody. A 41-year-old woman was experiencing excessive daytime sleepiness. Cataplexy was not evident. One month after, she became aware of anhidrosis on the left side of her body including the face. The following month, she was admitted to our hospital because of hypersomnia and anhidrosis that extended throughout her entire body. Physical and neurological examination revealed hypotension (93/62 mmHg) and dry skin. Brain magnetic resonance imaging (MRI) showed a high signal intensity area around the third ventricle on fluid-attenuated inversionrecovery image (Fig. 1a). Multiple sleep latency test showed shortening of the mean sleep latency (4.8 min; normal: [8 min) and sleep-onset REM periods. Lumbar puncture showed only a decrease of CSF hypocretin-1 levels (177 pg/ml, normal:[200 pg/ml). Serum anti-AQP4 antibody was positive. Although sympathetic skin responses (SSR) were absent in all limbs (Fig. 1c), intracutaneous acetylcholine injection caused normal sweating reaction. The patient was diagnosed with NMO spectrum disorders having narcolepsy and anhidrosis, secondary to hypothalamic lesions associated with anti-AQP4 antibody, and treated with intravenous methylprednisolone (1 g/day) for 3 days, followed by oral prednisolone (1 mg/kg/day). After treatment, her excessive sleepiness and anhidrosis disappeared in a few days. MRI showed improvement of the abnormal intensity area (Fig. 1b), and CSF hypocretin-1 levels had recovered to 213 pg/ml. Moreover, repeated tests of SSR showed positive responses (Fig. 1d). Anhidrosis of the entire body was detected and confirmed by SSR in our patient associated with anti-AQP4 antibody as well as symptomatic narcolepsy. After treatment, the reduced CSF hypocretin-1 levels returned to normal in parallel with improvement of excessive daytime sleepiness, similar to previously reported NMO cases [3]. The hypothalamus is the highest level of integration of autonomic function; tumors, trauma, inflammation, or vascular disorders in this structure are known to cause autonomic dysfunctions such as hypothermia or abnormal T. Sekiguchi S. Ishibashi T. Kubodera J. Fukabori T. Yokota (&) H. Mizusawa Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan e-mail: tak-yokota.nuro@tmd.ac.jp

Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia.

The human discs, large homolog 1 gene (DLG1) is mapped to the schizophrenia-susceptibility locus 3q29, and it encodes a scaffold protein that interacts with the N-methyl-D-aspartate receptor presumably dysregulated in schizophrenia. In the current study, we have newly identified a splicing variant of DLG1, which is transcribed from an unreported 95-base-pair exon (exon 3b) and is labeled 3b(+). We investigated the mRNA expression of 3b(+) in the post-mortem dorsolateral prefrontal cortices of patients with psychiatric disorders, obtained from The Stanley Medical Research Institute, and examined the potential association of the expression with the genotype of the single-nucleotide polymorphism (SNP) rs3915512 located within exon 3b. A real-time quantitative reverse transcriptase-polymerase chain reaction revealed that the mRNA levels of 3b(+) were significantly reduced in patients with early-onset schizophrenia (onset at <18 years old, P=0.0003) but not in those with non-early-onset schizophrenia, early-onset or non-early-onset bipolar disorder or in the controls. Furthermore, the genotype at the rs3915512 SNP was closely associated with the levels of 3b(+) mRNA expression. It is inferred that the T allele fails to meet the exonic splicing enhancer consensus, thus resulting in skipping of exon 3b, leading to the expression of 3b(−) (the previously known DLG1 variant) but not 3b(+). Because all the subjects with early-onset schizophrenia in the current study possess the T/T genotype, the reduced level of the DLG1 3b(+) transcript may be involved in the susceptibility and/or pathophysiology of early-onset schizophrenia.

Comparison of cerebral blood flow in oral somatic delusion in patients with and without a history of depression: a comparative case series

BackgroundA significant number of patients visit dental clinics because of unusual oral sensations for which no physical cause can be found. Such patients are recognized as having oral somatic delusion (OSD). OSD may be either primary (monosymptomatic) or secondary to another disease, such as depression or cerebral infarction. Although the presenting complaints of patients with primary and secondary OSD are nearly indistinguishable, symptoms in patients with secondary OSD seem to be resistant to treatment compared with those in patients with primary OSD. Moreover, right dominant cerebral blood flow (CBF) has been reported in patients with primary OSD, but the difference in CBF between patients with primary and secondary OSD remains unclear. The aim of this study was to assess the differences in clinical characteristics and CBF distribution between patients with monosymptomatic OSD (non-depression group) and OSD in conjunction with remitted depression (depression group).MethodsParticipants were 27 patients of a psychosomatic dentistry clinic, all diagnosed with OSD. They were categorized into either the non-depression group (17 patients) or the depression group (10 patients) on the basis of assessments by their personal medical providers. CBF was examined using single-photon emission computed tomography.ResultsThere was no difference in clinical presentation between the two groups. A significant right dominant asymmetry in the temporal and posterior cerebral regions was observed in both groups. In the central region, a right dominance was seen in the non-depression group, while a left dominance was seen in the depression group. Moreover, the mean regional CBF values for patients in the depression group were significantly lower in several regions (including bilateral callosomarginal, precentral, angular, temporal, posterior cerebral, pericallosal, lenticular nucleus, thalamus, and hippocampus; and right central and cerebellum) than for patients in the non-depression group.ConclusionThese results suggest that the temporal and posterior cerebral regions are involved in in the pathophysiology of OSD, regardless of depression history, and that widespread CBF reduction is a characteristic of remitted depression.

Oral Dysesthesia Rating Scale: a tool for assessing psychosomatic symptoms in oral regions

BackgroundThe concept of cenesthopathy was first introduced by Dupré and Camus in 1907 to describe clinically unexplainable bodily sensations mainly attributed to psychiatric pathology. If it occurs in oral regions, it is termed oral cenesthopathy and it has been of special interest to psychiatrists and dentists. While there is no independently defined criteria for this condition, which is classified as either a delusional or a somatoform disorder, clinical practice and research require a standard scale to measure and rate its symptoms. In this study, we included any types of psychosomatic symptoms in oral regions as oral dysesthesia, and developed an Oral Dysesthesia Rating Scale (Oral DRS) and evaluated its validity and reliability as an assessment tool.MethodsThe scale was developed based on literature review and extensive clinical experience. Twelve reviewers assessed relevancy of each item to oral dysesthesia symptoms by 1–4 scoring scale and item content validity index was computed. To evaluate the inter-rater reliability of Oral DRS, pairs of raters administered the scale to 40 randomly selected patients with complaints of oral dysesthesia symptoms and Cohen’s weighted kappa coefficient was determined for each item.ResultsThe scale assesses the severity of feelings of foreign body [A1], exudation [A2], squeezing-pulling [A3], movement [A4], misalignment [A5], pain [A6], and spontaneous thermal sensation or tastes [A7], and the degree of impairment in eating [B1], articulation [B2], work [B3], and social activities [B4] on a scale of 0–5. Items A1, A2, A3, A4, B3, and B4 demonstrated acceptable content validity. Inter-rater reliabilities were good or excellent for all items evaluated.ConclusionThe Oral DRS can help define the nosography of clinically unexplainable oral dysesthesia through further case evaluation and clinical research and facilitate devising of treatment modalities.

Two Cases of Oral Somatic Delusions Ameliorated With Brain Perfusion Asymmetry: A Case Report

Background Oral cenesthopathy is the complaint of abnormal oral sensation where no underlying organic cause can be identified. It is also called oral dysesthesia or oral somatic delusion and classified as delusional disorder, somatic type. The patients with oral cenesthopathy show right > left asymmetric regional cerebral blood flow (rCBF) in the broad brain region. However, the studies scrutinizing the rCBF change before and after the successful treatment are still a few so far. Case We present 2 cases of oral cenesthopathy, who responded well to aripiprazole. The asymmetric rCBF patterns were attenuated after successful treatment in both cases. Conclusions We found a marked improvement of oral cenesthopathy with aripiprazole. It is suggested that right > left rCBF asymmetry in the frontal and temporal lobes and thalamus, and the dopaminergic and serotonergic dysfunctions are involved in the pathology of oral cenesthopathy.

Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus

The synapse‐associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N‐methyl‐D‐aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40‐fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate‐specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non‐early onset schizophrenia, whose onset‐age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early‐onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta‐analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate‐specific exon of the gene in the schizophrenia‐associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.