Do the epilepsies,pain syndromes,and affective disorders share common kindling-like mechanisms?

Kindling, in the classical sense, involves progressively increasing responsivity to the intermittent repetition of the same 1-s subthreshold electrical stimulation over time, with the amygdala being the area most frequently studied. Such repeated subthreshold stimulation is associated with: lowering of the after-discharge (AD) threshold; lengthening and spread of the AD; marked seizure stage progression culminating in full-blown tonic-clonic forelimb convulsions with rearing and falling; and evolution from triggered to spontaneous seizures. This evolving process concomitantly involves changes in the spatio-temporal expression of immediate early genes (IEGs), neurotrophic factors, and late effector genes (LEGs), and an associated changing pattern of effectiveness of different pharmacological interventions. Since seizures are the paradigmatic behavioral manifestation of kindling, some types of pharmacological seizures, such as those induced by the local anesthetics cocaine and lidocaine, and some epileptic syndromes, are most likely homologously modeled by kindling. However, since non-epileptiform syndromes, such as recurrent episodes of affective illness and some pain syndromes possess non-homogenous elements of kindling-like evolution, some of the principles involved in kindling progression may, nonetheless, be pertinent to the understanding and treatment of these syndromes. For example, one could attempt to distinguish between the genes involved in the primary pathological processes of syndrome evolution versus those that are secondary and adaptive; such a differentiation could have important implications for the development of therapeutic approaches targeted to suppressing or enhancing these alterations, respectively. In these instances, inferences drawn from the kindling model are necessarily indirect and circumscribed because different neuroanatomical and biochemical processes are likely involved in the evolution of each neuropsychiatric syndrome. Given these recognized limitations of non-homologous models, kindling may still provide insights into the longitudinal course, progression, and treatment of some neuropsychiatric syndromes that can then be directly tested in the clinic.     

Is impulsivity a common trait in bipolar and unipolar disorders?

Henna E, Hatch JP, Nicoletti M, Swann AC, Zunta‐Soares G, Soares JC. Is impulsivity a common trait in bipolar and unipolar disorders?
Bipolar Disord 2013: 00: 000–000. © 2013 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Impulsivity is increased in bipolar and unipolar disorders during episodes and is associated with substance abuse disorders and suicide risk. Impulsivity between episodes predisposes to relapses and poor therapeutic compliance. However, there is little information about impulsivity during euthymia in mood disorders. We sought to investigate trait impulsivity in euthymic bipolar and unipolar disorder patients, comparing them to healthy individuals and unaffected relatives of bipolar disorder patients. Methods: Impulsivity was evaluated by the Barratt Impulsiveness Scale (BIS‐11A) in 54 bipolar disorder patients, 25 unipolar disorder patients, 136 healthy volunteers, and 14 unaffected relatives. The BIS‐11A mean scores for all four groups were compared through the Games–Howell test for all possible pairwise combinations. Additionally, we compared impulsivity in bipolar and unipolar disorder patients with and without a history of suicide attempt and substance abuse disorder. Results: Bipolar and unipolar disorder patients scored significantly higher than the healthy controls and unaffected relatives on all measures of the BIS‐11A except for attentional impulsivity. On the attentional impulsivity measures there were no differences among the unaffected relatives and the bipolar and unipolar disorder groups, but all three of these groups scored higher than the healthy participant group. There was no difference in impulsivity between bipolar and unipolar disorder subjects with and without suicide attempt. However, impulsivity was higher among bipolar and unipolar disorder subjects with past substance use disorder compared to patients without such a history. Conclusions: Questionnaire‐measured impulsivity appears to be relatively independent of mood state in bipolar and unipolar disorder patients; it remains elevated in euthymia and is higher in individuals with past substance abuse. Elevated attentional and lower non‐planning impulsivity in unaffected relatives of bipolar disorder patients distinguished them from healthy participants, suggesting that increased attentional impulsivity may predispose to development of affective disorders, while reduced attentional impulsivity may be protective.     

Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia?

Over recent years the gene DTNBP1 (chromosome 6p24-22) has emerged as one of the most promising candidate genes for schizophrenia. In this article, we review the current genetic evidence that implicates DTNBP1 as a schizophrenia-susceptibility gene. While there is now impressive support from genetic association studies, it is important to remain aware that the actual DTNBP1 susceptibility variants have not been identified. While functional analyses have allowed us to speculate their likely function, only when they are identified will we be able to confidently specify the type of altered gene function that is relevant to schizophrenia pathogenesis. This we hope will then open up new vistas for neurobiological research, allowing us to study the exact contribution of DTNBP1 in schizophrenia, its relationships with various aspects of the phenotype, and the potential of epistatic interactions with other genes, as well as functional interactions between the gene products.     

Apoptosis and schizophrenia: is the tumour suppressor gene, p53, a candidate susceptibility gene?

This paper reviews the six published incidence studies of the relative risk of cancer in patients with schizophrenia compared with the general population. These studies used: incidence data, register case ascertainment, and controlled for age and sex. It is concluded that schizophrenia is associated with a lower risk of developing cancer. The role of apoptosis (programmed cell death) in cancer and brain development is briefly described. The possibility is explored that increased apoptosis may account for neurodevelopmental abnormalities as well as tumour resistance associated with schizophrenia. The authors propose that p53, a tumour suppressor gene central to regulation of apoptosis, should be investigated as a candidate susceptibility gene in schizophrenia.     

Do obsessive–compulsive disorder and Tourette syndrome share a common susceptibility gene? An association study of the BDNF Val66Met polymorphism in the Chinese Han population

Objectives. We explored the association between the BDNF Val66Met polymorphism and susceptibility to both obsessive–compulsive disorder (OCD) and Tourette syndrome (TS) in the Chinese Han population. Methods. Genotyping for the BDNF Val66Met polymorphism was performed in 321 OCD patients and 426 healthy control subjects and case–control association study data were analysed. Additionally, we evaluated the genetic contribution of this variant in 331 TS patients (including 267 TS trios) and 519 controls using the transmission disequilibrium test (TDT) and case–control study. Results. A statistically significant difference was found in the genetic contribution of the BDNF Val66Met polymorphism between both the OCD (χ² = 7.50, P = 0.023 by genotype; χ² = 6.67, P = 0.01 by allele) and TS (χ² = 6.76, P = 0.03 by genotype; χ² = 4.27, P = 0.04 by allele), and control groups. TDT and GHRR analysis for TS trios also showed a significant transform disequilibrium of this polymorphism (TDT: χ² = 3.96, P = 0.05; HHRR: χ² = 4.33 P = 0.04; GHRR: χ² = 5.74, P = 0.02; χ² = 0.98, P = 0.37). There was also a significant gender trend between patients and controls in female cases for OCD and in male cases for TS. Conclusions. Our study supports the involvement of the BDNF Val66Met polymorphism as a common genetic susceptibility for OCD and TS in the Chinese Han population, showing specific gender trends.     

Do obsessive-compulsive patients and abstinent heroin addicts share a common psychophysiological mechanism?

BACKGROUND/AIM: Working memory (WM) and attentional deficits have been implicated in the pathophysiology of both obsessive-compulsive disorder (OCD) and opioid addiction. The P300 component of event-related potentials (ERPs) is considered as an index of on-line updating of WM and/or attentional operations involved in this function. The present study aimed at comparing the P300 elicited during a WM test in patients with prolonged heroin abstinence, those with OCD and healthy controls, in order to demonstrate possibly common underlying psychophysiological mechanisms. METHODS: The P300 component was evaluated during the anticipatory period of a WM test in 20 patients characterized by a past history of opioid dependence (6 months abstinence), in 18 OCD patients, and 20 healthy subjects matched for age, sex and educational level. RESULTS: The two patient groups showed a considerable reduction of the P300 amplitudes, located at the right frontal area as compared with healthy controls. The abstinent heroin addicts exhibited a significantly lower P300 amplitude at central frontal areas and a significantly higher P300 amplitude at the left occipital region relative to the other two groups. Furthermore, the abstinent group showed a notable delay of P300 latency relative to controls and OCD patients at the right occipital region. Moreover, the OCD patients manifested a significant prolongation of P300 located at the central prefrontal area, relative to addicts and healthy controls. CONCLUSIONS: These findings point to considerable WM and/or attentional deficits in the long-term abstinent syndrome of heroin misuse and OCD associated with distributed and prefrontal cortical circuits, respectively. Furthermore, the present findings suggest that both OCD and long-term abstinent heroin addicts may share a common impairment of WM and/or attention involving or affecting the right prefrontal areas.     

Do deep dyslexia, dysphasia and dysgraphia share a common phonological impairment?

This study directly compared four patients who, to varying degrees, showed the characteristics of deep dyslexia, dysphasia and/or dysgraphia--i.e., they made semantic errors in oral reading, repetition and/or spelling to dictation. The "primary systems" hypothesis proposes that these different conditions result from severe impairment to a common phonological system, rather than damage to task-specific mechanisms (i.e. grapheme-phoneme conversion). By this view, deep dyslexic/dysphasic patients should show overlapping deficits but previous studies have not directly compared them. All four patients in the current study showed poor phonological production across different tasks, including repetition, reading aloud and spoken picture naming, in line with the primary systems hypothesis. They also showed severe deficits in tasks that required the manipulation of phonology, such as phoneme addition and deletion. Some of the characteristics of the deep syndromes - namely lexicality and imageability effects - were typically observed in all of the tasks, regardless of whether semantic errors occurred or not, suggesting that the patients' phonological deficits impacted on repetition, reading aloud and spelling to dictation in similar ways. Differences between the syndromes were accounted for by variation in other primary systems--particularly auditory processing. Deep dysphasic symptoms occurred when the impact of phonological input on spoken output was disrupted or reduced, either as a result of auditory/phonological impairment, or for patients with good phonological input analysis, when repetition was delayed. 'Deep' disorders of reading aloud, repetition and spelling can therefore be explained in terms of damage to interacting primary systems such as phonology, semantics and vision, with phonology playing a critical role.     

Sleep disturbances in schizophrenia spectrum and bipolar disorders – a transdiagnostic perspective

BackgroundSleep disturbances are prevalent in severe mental disorders but their type and frequency across diagnostic categories has not been investigated in large scale studies.MethodsParticipants with Schizophrenia spectrum disorders (SCZ, (N = 617)), Bipolar disorders (BD, (N = 440)), and Healthy Controls (HC, (N = 173)) were included in the study. Sleep disturbances (insomnia, hypersomnia and delayed sleep phase) were identified based on items from the Inventory of Depressive Symptoms – Clinician rated scale. Clinical symptoms were assessed with the Positive and Negative Syndrome scale and level of functioning with the Global assessment of Functioning scale.ResultsThe rate of any sleep disturbance was 78% in SZ, 69% in BD and 39% in HC. Insomnia was the most frequently reported sleep disturbance across all groups. Both diagnostic groups reported significantly more of any sleep disturbances than HC (P < 0.001). Having a sleep disturbance was associated with more severe negative and depressive symptoms and with lower functioning across diagnostic groups (P < 0.001, η² = 0.0071). Hypersomnia was the only sleep disturbance associated with previous treatment history.ConclusionSleep disturbances, including insomnia, hypersomnia and delayed sleep phase, are frequent in SCZ and BD, and associated with more severe clinical symptomatology across diagnostic groups. This suggests that sleep disturbance is a clinically relevant transdiagnostic phenomenon.     

Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?

Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR) = 1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09–1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR = 2.03 for AA versus CC genotype carriers, CI: 1.07–3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders.     

Do olfactory reference syndrome and jiko-shu-kyofu (a subtype of taijin-kyofu) share a common entity?

OBJECTIVE: Olfactory reference syndrome (ORS) in the Western literature is characterized as preoccupation with the idea that the body emits a foul odor. Japanese patients with a feature similar to ORS have long been recognized as jiko-shu-kyofu, which is believed to be a culture-bound syndrome and specific to Japan. The aim of the study was to clarify the relationship between the two separate syndromes that had independently been recognized in culturally different settings. METHOD: The phenomenology and treatment of seven patients with jiko-shu-kyofu were described. A feature of jiko-shu-kyofu was then compared with that of ORS. RESULTS: In our cases, clinical characteristics of jiko-shu-kyofu such as symptomatology, insight, and pharmacotherapy response were found identical to those of ORS except for the onset at relatively younger ages. CONCLUSION: Jiko-shu-kyofu and ORS may share a common clinical entity, hence the former is not a culturally distinctive disorder.     

Theory of mind impairment: a distinct trait‐marker for schizophrenia spectrum disorders and bipolar disorder?

Objective: The aim of this study was to critically review the literature in order to determine if Theory of Mind (ToM) impairment can be considered a trait‐marker for schizophrenia spectrum disorders and bipolar disorder (BD). Method: After a thorough literature search, we reviewed the empirical studies investigating ToM impairments in remitted schizophrenia patients, first episode patients, subjects at high‐risk (HR) for psychosis and first‐degree relatives of schizophrenia patients. Studies investigating ToM impairment in other schizophrenia spectrum conditions, affective psychosis and BD were also reviewed. Results: ToM abnormalities exist at onset and continue throughout the course of schizophrenia, persist into remission, and while less severe, are apparent in HR populations. Mentalizing impairments are also observed in other forms of psychotic illness and BD. Conclusion: Mentalizing impairment in schizophrenia spectrum disorders and BD might reflect underlying general cognitive deficits and residual symptom expression, rather than representing a specific trait‐marker.     

Do child psychiatrists in Germany diagnose bipolar disorders in children and adolescents? Results from a survey

OBJECTIVES: There is a controversy about the prevalence of childhood bipolar disorders (BD). Based on discrepant results, we studied if German psychiatrists in outpatient settings diagnose BD in children and adolescents at all, and if there are possible correlates of the diagnoses of pediatric BD. We also asked how often typical manic symptoms (e.g. elated mood) are actually seen in attention deficit hyperactivity disorder (ADHD) patients. METHODS: Provided by the medical register we had a complete list of all 251 psychiatrists in the area. Using a questionnaire we asked if and how often they diagnose BD among children and adolescents and how often they observe manic-like symptoms in children with ADHD (response rate 61%). RESULTS: While 63% of all psychiatrists have diagnosed BD in adolescents, only 7.8% did so in children. Age and therapeutic approach of the psychiatrists were associated with the likelihood of having diagnosed BD in children. Furthermore some typical bipolar symptoms were also present in ADHD patients. CONCLUSIONS: Our study only relied on self-reports of the psychiatrists about the diagnoses and number of cases, but BD in children seems to be rarely diagnosed in outpatient settings in Germany. The design of our study, however, cannot resolve the questions what the reasons are for this low rate of BD diagnoses, e.g. misdiagnoses, overlooking comorbidity or referral strategies. Epidemiological studies are needed and should consider multiple follow-ups.     

High-level gait and balance disorders in the elderly: a midbrain disease?

The pathophysiology of gait and balance disorders in elderly people with ‘higher level gait disorders’ (HLGD) is poorly understood. In this study, we aimed to identify the brain networks involved in this disorder. Standardised clinical scores, biomechanical parameters of gait initiation and brain imaging data, including deep white matter lesions (DWML) and brain voxel-based morphometry analyses, were assessed in 20 HLGD patients in comparison to 20 age-matched controls. In comparison to controls, HLGD patients presented a near-normal preparatory phase of gait initiation, but a severe alteration of both locomotor and postural parameters of first-step execution, which was related to ‘axial’ hypokinetic-rigid signs. HLGD patients showed a significant grey matter reduction in the mesencephalic locomotor region (MLR) and the left primary motor cortex. This midbrain atrophy was related to the severity of clinical and neurophysiologically determined balance deficits. HLGD patients also showed a reduction in speed of gait, related to ‘appendicular’ hypokinetic-rigid signs and frontal-lobe-like cognitive deficits. These last two symptoms were correlated with the severity of DWML, found in 12/20 HLGD patients. In conclusion, these data suggest that the gait and balance deficits in HLGD mainly result from the lesion or dysfunction of the network linking the primary motor cortex and the MLR, brain regions known to be involved in the control of gait and balance, whereas cognitive and ‘appendicular’ hypokinetic-rigid signs mainly result from DWML that could be responsible for a dysfunction of the frontal cortico-basal ganglia loops.     

Do anxiety and depression have a common pathophysiological mechanism?

OBJECTIVE: To review, examine and propose a common mechanism for anxiety and depression based on modifications observed in neurotransmitter systems (mainly noradrenergic and serotonergic) and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHOD: The relevant papers were identified by searches in Medline, Excerpta Medica, PsychLIT and other databases. The primary reports were reviewed and classified into animal and human data concerning: modifications of the monoamine receptors in anxiety and depression, pathophysiology of endocrine factors in anxiety and depression, pathophysiology of the hypothalamic-pituitary-adrenal (HPA) axis and the pathophysiology of the HPA dysregulation in anxiety and in depression. In addition, a proposed model of a neuroendocrine continuum for anxiety and depression, in which anxiety occurs first during the life course and major depressive episodes occur later, was examined. RESULTS: Based on the available literature, increased concentrations of corticotropin-releasing factor (CRF) in the cerebrospinal fluid has been reported in both anxiety and depression. However, release of other peptides or hormones of the HPA axis is regulated differently in the two disorders. Anxiety is characterized by hypocortisolemia, supersuppression after dexamethasone and increased numbers of glucocorticoid receptors, whereas depression is characterized by hypercortisolemia, nonsuppression after dexamethasone and decreased numbers of glucocorticoid receptors. A 'neuroendocrine continuum' model is proposed to explain these differences. A general desensitization of CRF receptors at pituitary, limbic (amygdala) and cortical as well as hippocampal levels could be secondary to the loss of hippocampal inhibition resulting from hippocampal damage linked to repeated stressing events. CONCLUSION: The proposed hypothesis remains to be tested by examination of either the changes in receptors and neurotransmission or the mechanisms underlying the dysregulation of endocrine factors.     

Association study of schizophrenia spectrum disorders and dopamine D3 receptor gene: is schizoaffective disorder special?

Alterations in dopamine neurotransmission have been hypothesized to play a role in the etiology of schizophrenia. We considered the dopamine D3 receptor gene on chromosome 3 as a candidate gene for an association analysis. We compared PCR-based genotype markers for healthy controls (n=120) and patients (n=95) with schizophrenia and schizophrenia spectrum disorders as diagnosed by consensus according to DSM-III-R. Our results possibly indicate an association of schizoaffective disorder with DRD3 homozygosity (P=0.056).     

How common are seizures in the heidenhain variant of creutzfeldt-jakob disease? A case report and systematic review

The Heidenhain variant of Creutzfeld-Jakob disease (HvCJD) is a relentlessly progressive and fatal neurodegenerative disorder characterised by prominent visual features early in its clinical course. However, seizures are uncommonly reported in HvCJD. The case history of a patient admitted to our institution with HvCJD and seizures is described followed by a systematic review of the association between HvCJD and seizures. A systematic search of the databases Medline, PubMed, and PsycInfo was conducted, from inception to November 2019, using keywords relating to ‘Creutzfeldt-Jakob disease’ and ‘Heidenhain variant’, to ascertain the frequency of seizures in HvCJD, as well as, seizure semiology and electrographic features. The Preferred Items Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in the construction of this systematic review. All studies, including case reports of patients who met the diagnostic criteria for HvCJD where details pertaining to clinical presentation, imaging, biochemical and EEG findings were available were included. There were 46 articles reporting on a total of 73 patients. Seizures occurred in only four out of 73 cases (5.5%). The semiology of these seizures were focal motor seizures with or without secondary generalisation and occipital lobe seizures. Imaging and electrographic findings were most commonly abnormal in the posterior cerebral cortices (in particular the occipital and occipito-parietal regions). This systematic review suggests that seizures are uncommon in HvCJD despite the frequency of imaging and electrographic abnormalities in the posterior cerebral regions. A key limitation of this systematic review is the variability of publications in terms of incomplete reporting of clinical data, in particular potential under-reporting of seizures, as well as follow up, which may have contributed to the lower frequency of seizures reported in patients with HvCJD.     

Is there a gender difference on the association between informal work and common mental disorders?

Economic activity in Brazilian women has been increasing in recent years, particularly in the form of under- and self-employment, which allows more flexibility in the work schedule and facilitates part-time work, a crucial issue for women reconciling family duties and the need for a remunerated occupation. This paper investigates the gender difference in the association between employment status and common mental disorders (CMD). A cross-sectional survey of a random sample of private households included 683 adults aged 15 years and over living in Olinda, Brazil. The self-reporting questionnaire (SRQ-20) was used to estimate the prevalence of CMD. The association between unemployment and CMD for men (OR=1.77, 95% CI 0.8–3.9) was in the same direction as that found for women (OR=2.66, 95% CI 1.1–6.3), but not significant. In contrast to this, while women working in the informal sector were more likely to be a case of CMD than formal workers (OR=3.02, 95% CI 1.3–7.2), no difference was found for informally working men (OR=1.08, 95% CI 0.5–2.4). The estimated OR for female informal workers was out of the 95% confidence intervals of the corresponding OR estimated for males, and the test for interaction was statistically significant (p=0.04). From a policy perspective, the value of encouraging people to take informal work depends both on how quickly individuals can be moved out of unemployment into informal work compared to other destinations, and how well individuals fare once in informal work. The results of the present study suggest that working outside the protection of employment legislation and with limited opportunity for skill use may be a risk for women’s mental health.