The severity of psychiatric disorders

The issue of the severity of psychiatric disorders has great clinical importance. For example, severity influences decisions about level of care, and affects decisions to seek government assistance due to psychiatric disability. Controversy exists as to the efficacy of antidepressants across the spectrum of depression severity, and whether patients with severe depression should be preferentially treated with medication rather than psychotherapy. Measures of severity are used to evaluate outcome in treatment studies and may be used as meaningful endpoints in clinical practice. But, what does it mean to say that someone has a severe illness? Does severity refer to the number of symptoms a patient is experiencing? To the intensity of the symptoms? To symptom frequency or persistence? To the impact of symptoms on functioning or on quality of life? To the likelihood of the illness resulting in permanent disability or death? Putting aside the issue of how severity should be operationalized, another consideration is whether severity should be conceptualized similarly for all illnesses or be disorder specific. In this paper, we examine how severity is characterized in research and contemporary psychiatric diagnostic systems, with a special focus on depression and personality disorders. Our review shows that the DSM‐5 has defined the severity of various disorders in different ways, and that researchers have adopted a myriad of ways of defining severity for both depression and personality disorders, although the severity of the former was predominantly defined according to scores on symptom rating scales, whereas the severity of the latter was often linked with impairments in functioning. Because the functional impact of symptom‐defined disorders depends on factors extrinsic to those disorders, such as self‐efficacy, resilience, coping ability, social support, cultural and social expectations, as well as the responsibilities related to one's primary role function and the availability of others to assume those responsibilities, we argue that the severity of such disorders should be defined independently from functional impairment.     

Stress Impacts the Regulation Neuropeptides in the Rat Hippocampus and Prefrontal Cortex

Adverse life experiences increase the lifetime risk to several stress‐related psychopathologies, such as anxiety or depressive‐like symptoms following stress in adulthood. However, the neurochemical modulations triggered by stress have not been fully characterized. Neuropeptides play an important role as signaling molecules that contribute to physiological regulation and have been linked to neurological and psychiatric diseases. However, little is known about the influence of stress on neuropeptide regulation in the brain. Here, we have performed an exploratory study of how neuropeptide expression at adulthood is modulated by experiencing a period of multiple stressful experiences. We have targeted hippocampus and prefrontal cortex (PFC) brain areas, which have previously been shown to be modulated by stressors, employing a targeted liquid chromatography‐mass spectrometry (LC‐MS) based approach that permits broad peptide coverage with high sensitivity. We found that in the hippocampus, Met‐enkephalin, Met‐enkephalin‐Arg‐Phe, and Met‐enkephalin‐Arg‐Gly‐Leu were upregulated, while Leu‐enkephalin and Little SAAS were downregulated after stress. In the PFC area, Met‐enkephalin‐Arg‐Phe, Met‐enkephalin‐Arg‐Gly‐Leu, peptide PHI‐27, somatostatin‐28 (AA1‐12), and Little SAAS were all downregulated. This systematic evaluation of neuropeptide alterations in the hippocampus and PFC suggests that stressors impact neuropeptides and that neuropeptide regulation is brain‐area specific. These findings suggest several potential peptide candidates, which warrant further investigations in terms of correlation with depression‐associated behaviors.     

Perinatal nutrition interacts with genetic background to alter behavior in a parent‐of‐origin‐dependent manner in adult Collaborative Cross mice

Previous studies in animal models and humans have shown that exposure to nutritional deficiencies in the perinatal period increases the risk of psychiatric disease. Less well understood is how such effects are modulated by the combination of genetic background and parent‐of‐origin (PO). To explore this, we exposed female mice from 20 Collaborative Cross (CC) strains to protein deficient, vitamin D deficient, methyl donor enriched or standard diet during the perinatal period. These CC females were then crossed to a male from a different CC strain to produce reciprocal F1 hybrid females comprising 10 distinct genetic backgrounds. The adult F1 females were then tested in the open field, light/dark, stress‐induced hyperthermia, forced swim and restraint stress assays. Our experimental design allowed us to estimate effects of genetic background, perinatal diet, PO and their interactions on behavior. Genetic background significantly affected all assessed phenotypes. Perinatal diet exposure interacted with genetic background to affect body weight, basal body temperature, anxiety‐like behavior and stress response. In 8 of 9 genetic backgrounds, PO effects were observed on multiple phenotypes. Additionally, we identified a small number of diet‐by‐PO effects on body weight, stress response, anxiety‐ and depressive‐like behavior. Our data show that rodent behaviors that model psychiatric disorders are affected by genetic background, PO and perinatal diet, as well as interactions among these factors.     

Early warning biomarkers in major depressive disorder: a strategic approach to a testing question

Purpose: Identification of biomarkers in major depressive disorder (MDD) has proceeded in an extemporised manner. No single biomarker has been identified with utility in screening, diagnosis, prognosis, or monitoring, and screening tests have different characteristics than the other functions. Using chaos, bifurcation, and perturbation (CBP) theories, the aim is to identify biomarkers to aid clinicians in screening for MDD.

Materials and methods: MDD is a complex disorder; consequently, a reductionist approach to characterize the complex system changes found in MDD will be inchoate and unreliable. A holistic approach is used to identify biomarkers reflecting the tipping points seen before the catastrophic bifurcation that results in MDD.

Results: Applying CBP theories revealed skew, resistance to change, flickering, increased variance and autocorrelation as patterns of biomarkers. Integrals and differentials of extracellular and intracellular biomarkers were identified, specifically focussed on hypothalamo-pituitary axis (HPA) dysfunction, metabolic dysfunction, inflammation and mitochondrial oxidative stress, and tryptophan metabolism.

Conclusions: Applying CBP theories to the dysfunctional complex biological systems in MDD led to development of integrals and differentials of biomarkers that can be used in screening for MDD and planning future biomarker research, targeting intracellular and extracellular inflammation, HPA axis dysfunction, and tryptophan metabolism.     

Costs and benefits of admixture between foreign genotypes and local populations in the field

Admixture is the hybridization between populations within one species. It can increase plant fitness and population viability by alleviating inbreeding depression and increasing genetic diversity. However, populations are often adapted to their local environments and admixture with distant populations could break down local adaptation by diluting the locally adapted genomes. Thus, admixed genotypes might be selected against and be outcompeted by locally adapted genotypes in the local environments. To investigate the costs and benefits of admixture, we compared the performance of admixed and within‐population F1 and F2 generations of the European plant Lythrum salicaria in a reciprocal transplant experiment at three European field sites over a 2‐year period. Despite strong differences between site and plant populations for most of the measured traits, including herbivory, we found limited evidence for local adaptation. The effects of admixture depended on experimental site and plant population, and were positive for some traits. Plant growth and fruit production of some populations increased in admixed offspring and this was strongest with larger parental distances. These effects were only detected in two of our three sites. Our results show that, in the absence of local adaptation, admixture may boost plant performance, and that this is particularly apparent in stressful environments. We suggest that admixture between foreign and local genotypes can potentially be considered in nature conservation to restore populations and/or increase population viability, especially in small inbred or maladapted populations.     

Aß Facilitates LTD at Schaffer Collateral Synapses Preferentially in the Left Hippocampus

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Bilateral sensory disturbance after cortical spreading depression revealed by fluorescence imaging of voltage‐sensitive dye

Cortical spreading depression (CSD), a propagation wave of transient neuronal and glial depolarization followed by suppression of spontaneous brain activity, has been hypothesized to be the underlying mechanism of migraine aura and triggers the headache attack. Evidence from various animal models accumulates since its first discovery in 1944 and provides support for this hypothesis. In this paper, alterations of bilateral cortical responses are investigated in a mice migrainous model of CSD using voltage‐sensitive dye imaging under hindlimb and cortical stimulation. After CSD induction in the right hemisphere, bilateral sensory responses evoked by left hindlimb stimulation dramatically decreases, whereas right hindlimb stimulation can still activate bilateral responses with an increased response of the left hemisphere and a well‐preserved response of the right hemisphere. In addition, cortical neural excitability remains after CSD assessed by direct activation of the right hemisphere in spite of the sensory deficit under contralateral hindlimb stimulation. These results depict the sensory disturbance of bilateral hemispheres after CSD, which may be helpful in understanding how sensory disturbance occur during migraine aura.      

Long-term chemical castration induces depressive symptoms by suppressing serotonin expression in rats

Androgen deprivation therapy, also known as chemical castration, has been used as an adjunct to psychotherapy for sex offenders. Goserelin and bicalutamide are drugs used for chemical castration. Serotonin (5-hydroxytryptamine, 5-HT) is a key neurotransmitter involved in mood changes, such as depression. We investigated the effects of surgical and chemical castration on depressive symptoms in rats. Surgical castration was performed through a bilateral orchiectomy. Bicalutamide was administrated orally once a day for 84 consecutive days. Goserelin acetate was implanted subcutaneously into the anterior abdominal wall, and this implantation was repeated 3 times at 28-day intervals. Testosterone levels were detected by enzyme-linked immunosorbent assays. Sexual behaviors were analyzed by measuring mount latency, mount frequency, intromission latency, and intromission frequency. The forced swimming test was performed to evaluate rats’ depression status. To detect 5-HT and tryptophan hydroxylase (TPH)-positive cells in the dorsal raphe, immunohistochemistry for 5-HT and TPH and western blotting for 5-HT1A receptors and TPH were performed. Surgical castration and goserelin decreased testosterone levels and suppressed sexual behaviors. However, bicalutamide did not inhibit sexual behaviors, although it reduced testosterone levels to a limited extent. Both surgical and chemical castration induced depression in rats. The expression of 5-HT, TPH, and 5-HT1A receptors in the dorsal raphe was significantly decreased by both surgical castration and chemical castration via bicalutamide and goserelin. The present results showed that surgical and chemical castration for 12 weeks induced a depressive state in rats by inhibiting serotonergic function through 5-HT1A receptors.     

EVOLUTION OF GYNODIOECY AND MAINTENANCE OF FEMALES: THE ROLE OF INBREEDING DEPRESSION,OUTCROSSING RATES,AND RESOURCE ALLOCATION IN SCHIEDEA ADAMANTIS (CARYOPHYLLACEAE)

Levels of inbreeding depression, outcrossing rates, and phenotypic patterns of resource allocation were studied to examine their relative importance in the maintenance of high numbers of females in gynodioecious Schiedea adamantis (Caryophyllaceae), an endemic Hawaiian shrub found in a single population on Diamond Head Crater, Oahu. In studies of inbreeding depression in two greenhouse environments, families of hermaphrodites exhibited significant inbreeding depression (δ = 0.60), based on a multiplicative fitness function using seeds per capsule, germination, survival, and the inflorescence biomass of progeny. Differences between inbred and outcrossed progeny were smallest at the early stage of seeds per capsule and more pronounced at the later stages of survival and inflorescence production. These results are consistent with inbreeding depression caused by many mutations of small effect. Using allozyme analyses, the inbreeding coefficient of adult plants in the field was not significantly different from zero, implying that δ in nature may be equal to one. The single locus estimate of the outcrossing rate for hermaphrodites was 0.50 based on progeny that survived to flowering; corrected for the disproportionate loss before flowering of progeny from selfing, the adjusted outcrossing rate at the zygote stage was 0.32, suggesting that considerable selfing occurs in hermaphrodites. Females were totally outcrossed. When females and hermaphrodites were compared for reproductive output in the field, females produced over twice as many seeds per plant as hermaphrodites, primarily because females had far more capsules per inflorescence than hermaphrodites. Females had greater mass per seed than hermaphrodites in the field, either because of greater provisioning or reduced inbreeding depression. There was no significant differential mortality with respect to sex over a seven year period. The higher number of seeds per plant of females, combined with substantial inbreeding depression and relatively high selfing rates for hermaphrodites, are probably responsible for the maintenance of females in this population. The predicted frequency of females based on data for seed production, the adjusted selfing rate, and inbreeding depression is 42%, remarkably close to the observed frequency of 39%. High levels of inbreeding depression suggest that considerable quantitative genetic variation is present for traits affecting fitness in this population, despite low allozyme variability and a presumed founder effect.     

THE EFFECT OF INBREEDING IN DIPLOID AND TETRAPLOID POPULATIONS OF EPILOBIUM ANGUSTIFOLIUM (ONAGRACEAE): IMPLICATIONS FOR THE GENETIC BASIS OF INBREEDING DEPRESSION

The partial dominance model for the evolution of inbreeding depression predicts that tetraploids should exhibit less inbreeding depression than their diploid progenitors. We tested this prediction by comparing the magnitude of inbreeding depression in tetraploid and diploid populations of the herbaceous perennial Epilobium angustifolium (Onagraceae). Inbreeding depression was estimated in the greenhouse for three tetraploid and two diploid populations at four life stages. The mating system of a tetraploid population was estimated and compared to a previous estimate for diploids. Tetraploids showed less inbreeding depression than diploids at all life history stages, and these differences were significant for seed-set and cumulative fitness, but not for germination, survival, or plant dry mass at nine weeks. This result suggests that the genetic basis of inbreeding depression may differ among life stages. The primary selfing rate of the tetraploid population was r = 0.43, which is nearly identical to that of a diploid population (r = 0.45), indicating that differences in inbreeding depression between diploids and tetraploids are probably not due to differences in the mating system. Cumulative inbreeding depression, calculated from the four life history stages, was significantly higher for diploids () than for tetraploids (), supporting the partial dominance model of inbreeding depression.