Search

Background Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns. Methods This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3). Results Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders. Conclusions Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.

The cloning of the dopamine (DA) D2 receptor now permits the characterization and regulation of D2 messenger RNA (mRNA) in the brain. In this article, the authors describe their studies delineating the distribution of D2 receptor mRNA in the rodent and primate brain, and compare the distribution of message to D2 receptor binding sites. The effects of chronic DA agonist and antagonist treatment on D2 receptor mRNA are also presented, and provide insights into receptor regulation. Finally, the autoreceptor role of D2 receptors located in the midbrain is examined with a combination of 6-hydroxydopamine lesions and anatomic colocalization studies with tyrosine hydroxylase. These preclinical results provide a framework for subsequent investigation into the nature of D2 receptor gene expression in postmortem brains from patients with disorders putatively associated with dopaminergic dysfunction, especially schizophrenia. They also lay the groundwork for a more profound understanding of DA neurocircuitry by combining molecular biological and traditional anatomical techniques.

Studies of neurotransmitter kinetics based on intraventricular injections of radio-labeled metabolites have been limited by several problems, including the inability of most investigators to recover more than 45% of the infected isotope from brain homogenates within several minutes after the injection...

This article presents a series of experiments that involves the development of three novel strategies for human stress research and the utilization of these strategies to examine neurobehavioral processes of stress in healthy volunteers, schizophrenia, and affective illness. The first strategy involved intravenous 2-deoxy-D-glucose (2DG) administration, a glucoprivic stressor. We found that glucoprivic stress results in dissociation of hypothalamus-pituitary-adrenal (HPA), adrenomedullary, and sympathoneural activity. In addition, glucoprivic stress in neuroleptic-treated schizophrenic patients caused heightened dopamine activity, as reflected by increased plasma homovanillic acid (HVA) levels and decreased adaptive responses as assessed by decreased food consumption following 2DG administration. These data suggest that neuroleptics do not prevent stress-related increases in dopamine activity and that schizophrenia may be associated with abnormalities in the stress response. The second strategy assessed effects of uncontrollable and identical amounts of controllable stress in volunteers and depressed patients. In volunteers, it was found that uncontrollable in comparison to controllable stress results in specific behavioral and neuroendocrine alterations. Moreover, uncontrollable stress exposure in depressed patients in comparison to volunteers produced greater alterations in behavioral ratings and plasma cortisol levels and that the uncontrollable stress related increases in helplessness ratings and cortisol levels were significantly correlated. These data suggest that depressed patients may have increased sensitivity to uncontrollable stress and that there may be an important interrelationship between the cognitive deficits of depression and the heightened HPA axis activity observed in these patients. Lastly, we used a naturalistic strategy to examine mechanisms relating childhood parental loss and the development of adult affective illness and found that among subjects with early parental loss histories, those who developed adult psychiatric illness had increased resting plasma levels of cortisol and beta-endorphin (ir) as compared with subjects with early loss and no adult history of psychiatric illness. Moreover, increased HPA activity in adulthood was significantly related to poor childhood adjustment to parental loss. The implications of the results of these studies are discussed.

This article has been retracted at the request of John H. Krystal, MD, Editor of Biological Psychiatry, with agreement from all authors. See Elsevier Policy on Article Withdrawal ( https://www.elsevier.com/about/policies/article-withdrawal ). The authors discovered an error in the scoring of the ERP data in this article. Specifically, the ERP in the authors' acquisition and processing stream is live referenced to CZ, and then should be re-referenced in post-processing to TP9 and TP10, as described in the paper. However, the authors discovered that they had accidentally continued to include Cz along with TP9 and TP10 in the template to re-reference the ERP data in post-processing. The authors reprocessed all of the data with only TP9 and TP10 in the referencing, as originally described in the manuscript, and then re-ran all of the analyses. The majority of the key results remained the same in terms of significance and interpretation. The results continue to show that children in PCIT_ED show a greater increase in RewP as a function of treatment than the waitlist group; however, the correlation with the corrected data is in the same direction, but reduced in magnitude and no longer significant. Thus, a greater change in RewP is no longer significantly associated with a greater reduction in MDD symptoms. This error affects the abstract, the results, Table 2, Figures 1-3, discussion, and supplement. The authors voluntarily informed the Journal of this honest error upon its discovery. Because of the extent and nature of the changes to the paper, the editors and authors concluded that, to ensure maximum clarity and transparency, the only course of action was to retract this version of the paper. The authors revised the paper, which the Journal had re-reviewed. The new version was accepted and has been published: 10.1016/j.biopsych.2020.06.032.

Background: \ud Numerous behavioral studies have highlighted the contribution of visual perceptual deficits to the nonverbal cognitive profile of individuals with 22q11.2 deletion syndrome. However, the neurobiological processes underlying these widespread behavioral alterations are yet to be fully understood. Thus, in this paper, we investigated the role of neural oscillations toward visuoperceptual deficits to elucidate the neurobiology of sensory impairments in deletion carriers.\ud \ud Methods: \ud We acquired 125 high-density electroencephalography recordings during a visual grating task in a group of 62 deletion carriers and 63 control subjects. Stimulus-elicited oscillatory responses were analyzed with 1) time-frequency analysis using wavelets decomposition at sensor and source level, 2) intertrial phase coherence, and 3) Granger causality connectivity in source space. Additional analyses examined the development of neural oscillations across age bins.\ud \ud Results: \ud Deletion carriers had decreased theta-band (4–8 Hz) and gamma-band (58–68 Hz) spectral power compared with control subjects in response to the visual stimuli, with an absence of age-related increase of theta- and gamma-band responses. Moreover, adult deletion carriers had decreased gamma- and theta-band responses but increased alpha/beta desynchronization (10–25 Hz) that correlated with behavioral performance. Granger causality estimates reflected an increased frontal-occipital connectivity in the beta range (22–40 Hz).\ud \ud Conclusions: \ud Deletion carriers exhibited decreased theta- and gamma-band responses to visual stimuli, while alpha/beta desynchronization was preserved. Overall, the lack of age-related changes in deletion carriers implicates developmental impairments in circuit mechanisms underlying neural oscillations. The dissociation between the maturation of theta/gamma- and alpha/beta-band responses may indicate a selective impairment in supragranular cortical layers, leading to compensatory top-down connectivity.

This article has been retracted at the request of the Editor. Reason: The original second author of this paper, Roxana M. Gonzalez, has acknowledged that she misreported data supporting an exploratory mediation analysis reported at the end of the original paper. None of the co-authors participated in or had knowledge of the second author's actions. The second author cooperated fully in determining the scope and impact of her actions and in rectifying the research record.

Among the 26% of Americans that showed a 12-month prevalence for a DSM-IV psychiatric disorder in 2005, most suffered from anxiety disorders (18.1%), followed by mood disorders at 9.5% (1). Therefore, anxiety disorders affect nearly one fifth of the population directly in their lifetime, albeit with substantial variation in range of affliction. Despite the current availability of numerous pharmaceutical anxiolytic treatments, most exert only a temporary relief on acute symptomatology, whilst few traditional anxiolytic agents promote long-term alleviation of core symptoms such as the cognitive aspects of anxiety disorders. While a considerable amount of work has explored the role of GABA and GABA modulators in anxiety, more recently, pharmaceutical “anti-depressant” treatments (ADT) such as SSRI’s have been demonstrated as somewhat successful in treating anxiety disorders. Despite their indisputable contributions to psychiatric therapeutics, ADT’s have considerable limitations clinically, such as the prolonged latency (3–5 weeks of chronic administration) until core symptom relief is observed. Thus, there is an urgent need to define the neural systems that mediate anxiety and understand its pathophysiology, which would allow us to explore new treatment avenues. Recent work from the Akil laboratory has investigated a potential role for fibroblast growth factor 2 (FGF2) in the hippocampus in anxiety and mood disorders. FGF2, a potent central nervous system growth factor and glial mitogen, has been shown to play fundamental roles in growth of the cerebral cortex and hippocampus and genesis of excitatory neurons in these regions during development (2, 3). Patients with affective disorders including major depression and post-traumatic stress disorder have decreased hippocampal volume (4). Decreases in levels of FGF2 have been observed postmortem in humans that suffered from major depressive disorder (MDD), and, in rodents, increases in FGF2 have been reported in response to ADT treatment (5). In addition to serving a developmental role in building up hippocampal and cortical circuitry, FGF2 levels vary in response to acute changes in CNS homeostasis in adulthood. For example, FGF2 is increased in the hippocampus of animals that have undergone acute stressors, whereas repeated stress and/or chronic corticosterone treatment are associated with decreased levels of hippocampal FGF2 (6). However, alterations in FGF2 levels are not confined to “emotional” perturbations. Hypoxia upregulates both FGF1 and FGF2 in several regions (7) and the knockout of Fgf2 or Fgfr1 (one of the FGF receptors that is stimulated by FGF2) abolishes endogenous compensatory neurogenic responses that are induced after hypoxic or hypoxic/ischemic insults (8). Indeed, FGF2 is a potent neurogenic and trophic factor that improves the outcome of many types of injury. Despite an abundance of correlative evidence for a relationship between FGF2 and depression/anxiety behavior, a causal relationship has not been suggested until recently, when the Akil group showed that chronic peripheral administration of FGF2 in rats showing high anxiety has anxiolytic and potentially antidepressant-like effects (9). In “shRNA silencing of endogenous FGF2 in rat hippocampus increases anxiety behavior” (10), this group goes further by establishing a role for endogenous FGF2 in anxiety behavior by using RNA interference (RNAi) to knockdown FGF2 specifically in the hippocampus. In this paper, they first establish that levels of hippocampal FGF2 gene expression are positively correlated to levels of exhibited anxiety behavior on the elevated plus maze. Following this, they administered a lentivirus expressing short hairpin RNA (shRNA) targeting FGF2 bilaterally into the hippocampus and showed a significant knockdown of FGF2 limited to the DG and extending somewhat to the CA3. Silencing FGF2 in the hippocampus leads to significant increases in anxiety behavior on the elevated plus maze. Taken together, these data suggest that levels of FGF2 within the hippocampus signal overall allostatic load (11), or a sum of an individual’s net vulnerability and resilience to morbidity for anxiety or mood disorders (Figure 1). This is consistent with FGF2 being increased by neuroprotective events, acute stress, escapable shock and ADT treatment, suggesting that levels of this factor are regulated in postnatal life to maintain homeostasis through mechanisms that are still unknown. Conversely, chronic stress, chronic corticosteroid administration and inescapable shock all decrease FGF2 in the hippocampus and are associated with increased vulnerability and decreased resilience to anxiety and mood disorders. Of course, allostatic load is not only modulated by postnatal environmental events but also incorporates genetic vulnerability, prenatal events and epigenetic modifications, among others, that can all play contributory roles in disease morbidity. Interestingly, there is some evidence that FGF2 may also be related to these predisposing factors, as baseline levels of FGF2 have also been shown to differ between strains of rats that show differential anxiety levels, such that highly anxious animals (presumably as a result of strain differences in genetic and developmental factors) show lower levels of FGF2. Figure 1 Hippocampal FGF2 levels are correlated with events that mediate allostatic load for anxiety and mood disorder morbidity. Genetic predisposition, prenatal and postnatal environmental events all contribute to any given individual’s allostatic load, ... What could be linking these different roles of FGF2 in pre- and postnatal development? Biologically, FGF2 promotes the self-renewal of neural stem cells increasing the size of neural stem cell pools (12) and thus promotes neurogenesis and gliogenesis, both during embryogenesis and in adulthood (2, 6, 9, 12, 13). Perhaps it is not by chance that the hippocampus, in which FGF2 has been implicated in the regulation of anxiety, is also the region that plays a fundamental role in learning and memory through adult neurogenesis. Hippocampal neurogenesis has been also implicated in the pathophysiology of mood disorders. For example, ablation of hippocampal neurogenesis using focal irradiation blocks the effects of ADT treatment on anxious and depressive-like behavior in mice, an effect that appears to be inextricably linked to changes in learning and memory (14). The specific biological mechanisms through which FGF2 manifests its effects on mood and anxiety are still to be explored. Besides the role of FGF2 in neural stem cell self-renewal and increased new cell survival, this factor may potentially have other related or independent effects, any of which could presumably decrease vulnerability and increase resilience to anxiety/mood disorders. For example, FGF ligands and receptors promote synaptogenesis in the early postnatal period (15), and presumably some FGFs can continue to play a role in synaptic plasticity in adulthood. FGF2 has been shown to be instrumental in facilitating long-term learning and memory and potentiation of synapses, and in a recent paper, a role for FGF2 in mediating NMDAr dependant and independent extinction of conditioned fear has been proposed (16). Conditioned fear is at the core of many dysfunctional cognitive components involved in the development of mood and anxiety disorders. Extinction of conditioned fears (or at the very least, a decrease in salience) must occur during recovery. Therefore, it remains possible that the observed correlation of hippocampal FGF2 levels with behavioral tests of anxiety do not underlie the direct expression of anxiety behavior per se. Rather, FGF2 may also regulate the flexibility of learning and memory in the hippocampus, and facilitate recovery through extinction of cognitive changes associated with psychopathology and ultimately the learning of new associations. Despite the potential implications of the current study from Eren-Kocak et al., it is important to note that this study only examined the effects of blocking FGF2 on the elevated plus maze. Therefore, future studies will need to verify whether the behavioral effects of blocking FGF2 currently observed will generalize to other behavioral tests, such as novelty-suppressed feeding, open field, and light-dark box. Moreover, despite the indisputable wealth of knowledge that is obtained from animal models of mental illness, these models also have considerable limitations, particularly when assessing cognitive and emotional processes indirectly from behavioral performance. To date, all the work that has been done in humans has been largely correlative, and new pharmacological tools need to be established to test an etiological role for FGF2 in mood and anxiety disorders. In sum, the Akil group has demonstrated some first experimental evidence that FGF2 is causally implicated in the process of anxiety development, and theirs and previous data would suggest that FGF2 levels within the hippocampus are negatively correlated with expression of anxiety behavior; however, the mechanisms by which FGF2 exerts its effects on anxiety behavior remain to be determined. Given the substantial role for FGF2 in modulating stem cells self-renewal and neurogenesis within the hippocampus and the integral role for changes in hippocampal neurogenesis in regulating learning and memory processes, it is likely that FGF2 may act on anxiety behavior through stimulating or decreasing hippocampal neurogenesis. However, the study of FGFs is an ever-evolving field; future studies ablating FGF2 gene expression at different stages of development or adulthood will answer these questions.

In the first section of this paper several aspects of tardive dyskinesia (TD) (clinical, epidemiological, pharmacological) are reviewed. We propose that this syndrome is not the consequence of dopamine receptor proliferation, but results from damage or degeneration of striatal cholinergic interneurons. We suggest that this cellular damage is caused by prolonged overactivation of these neurons, which occurs when they are released from dopaminergic inhibition following neuroleptic administration. Overactivity of central cholinergic systems during akinetic and motor retarded depression could be a contributory cause. The predisposition to L-DOPA-induced peak-dose dyskinesia in Parkinson's disease may depend on the same type of striatal neuronal loss. In the second part of the paper, the subject of supersensitivity psychosis and drug-resistant schizophrenia is reviewed. These two syndromes, are commonly associated with TD, have similar predisposing factors and pharmacology to TD, and are potentially persistent. We suggest that these conditions also result from degeneration of cholinergic striatal interneurons following chronic neuroleptic administration. The efficacy of clozapine for such treatment-refractory psychoses is explained in terms of its blockade of D-1 dopamine receptors. Other drugs effective against refractory psychoses (e.g. risperidone) are predicted to reduce activation at D-1 receptors.

This paper is not a comprehensive review of the literature. Rather, it is a viewpoint based upon advances in other fields of medicine and genetics that may provide a model for guiding research in psychiatry. The paper discusses the major limitations of the medicines currently used to treat schizophrenia and bipolar illness. The limitations in our understanding of the molecular causes of these two illnesses and our lack of a clear mechanism of action for many of the medicines used to treat them continue to confound the field and impede progress towards finding novel treatments. Until the genetic bases of bipolar illness and schizophrenia are unambiguously identified, progress towards improved diagnosis and treatment will be retarded. An approach to identifying risk genes based upon association studies starting with very large sample sizes based upon currently available diagnoses of bipolar disorder and schizophrenia is advocated.

Child abuse is a non-specific risk factor associated with increased risk for a range of psychiatric and substance use disorders. The paper in this issue by Dannlowski and colleagues [1] adds to a growing body of literature on the mechanisms by which adverse early experiences confer vulnerability to psychiatric illness. The paper by Nikulina and colleagues [2] delineate further genetic and other factors that account for individual differences in the outcomes of adults who were abused as children. Dannlowski and colleagues [1] completed structural and functional magnetic resonance imaging (MRI) assessments in a large cohort of carefully screened healthy controls, with a proportion of subjects having histories of child abuse and neglect. While other studies have detected brain changes in trauma controls – individuals with a history of trauma who did not meet current criteria for Posttraumatic Stress Disorder (PTSD), the trauma controls in all prior studies included individuals with current and/or past psychiatric diagnoses other than PTSD [3]. The study by Dannlowski and colleagues is the first to examine the relationship between neuroimaging assessments and dimensional measures of child maltreatment in a healthy, never psychiatrically ill cohort. Given the association between child maltreatment and PTSD and major depression (MDD), they hypothesized a priori brain changes in areas implicated in these disorders. Consistent with this hypothesis, more severe childhood maltreatment was associated with increased amygdala activation during an emotion-processing task, and decreased volume in the hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and several other brain regions. Nikulina and colleagues [2] examined the interaction between monoamine oxidase-A (MAOA) genotype and child maltreatment in predicting MDD, dysthymia, and alcohol use disorder symptoms in adults. They identified sex and race effects that moderated the impact of MAOA genotype on adult outcomes. In the original paper by Caspi and colleagues [4], MAOA genotype was found to moderate the relationship between child maltreatment and antisocial behavior in males, with the high-activity MAOA allele protecting against psychopathology. Nikulina and colleagues reported significant three-way interactions that suggested the low-activity MAOA allele was protective in women and white participants when predicting depressive symptoms, and the high activity allele was protective against depressive symptoms in non-white maltreated females. The authors proposed that 1) the effects of MAOA genotype on antisocial behavior and mood are different; and 2) the direction of the effects of MAOA genotype is different for males and females, and whites and non-whites. Alternatively, they also suggested that their results might be “chance findings.” So, where do we go from here? Within the field there is a consensus that genes and environment interact to promote the development of depression and other stress-related psychiatric disorders, and agreement that the effects of severe stress are mediated by changes in brain structure and function. However, the nature of gene and environment interactions continues to be elusive, and the clinical significance of identified brain changes are not fully understood. What do we know, and what do we still need to learn to better understand the link between child maltreatment and psychiatric illness? What we know, Point 1: Many of the brain regions and circuits implicated in the pathophysiology of stress-related psychiatric problems are involved in the stress response As reviewed elsewhere and depicted in the simplified schematic in Figure 1, the brain responds to stress in an orchestrated manner [5, 6]. The stress response is initiated with the release of corticotropin releasing hormone (CRH) from the hypothalamus. CRH stimulates the release of adrenocorticotropin from the pituitary, which causes release of glucocorticoids (e.g., cortisol) from the adrenals. Glucocorticoids then stimulate CRH release from the amygdala, which in turn initiates norepinephrine release from the locus coeruleus and starts the sympathetic response to stress. The ACC, OFC, and mPFC play an important role in relaying information from primary sensory and association cortices to the amygdala and other subcortical structures, and inputs from these areas and the hippocampus help to attenuate the brain’s response to stress. The stress response also innervates the mesocortical and mesolimbic systems, which includes neurons of the ventral tegmentum area (VTA) that exert a suppressive effect on the stress system, and the nucleus accumbens (NAc), which receives inputs from VTA, amygdala, and mPFC. Figure 1 Brain Regions Involved In the Stress Response As depicted in Figure 1, many of the brain regions involved in the stress response are key structures in the emotion processing, reward, and executive function circuits --with dysregulation in these brain systems implicated in multiple stress-related psychiatric and substance use disorders [5]. For example, the amygdala, hippocampus, OFC, and mPFC, are key structures implicated in mood and anxiety disorders that are involved in the emotion processing circuit. The NAc and VTA, which receive inputs from multiple PFC areas, hippocampus, amygdala and hypothalamus, are key structures in the reward circuit and are involved in the pathophysiology of alcohol, substance use, and mood disorders. Given the overlap in the stress system and these other brain circuits, it is not surprising that severe stress in the form of child maltreatment is associated with increased risk for a range of psychiatric and substance use disorders. What we know, Point 2: The brain is not organized according to the psychiatric Diagnostic and Statistical Manual (DSM) There has been growing frustration with the limitations of the extant psychiatric nomenclature to delineate resilience and disease mechanisms. Consequently, the leadership of the National Institute of Mental Health (NIMH) established the Research Domain Criteria (RDoC) project, which has as its goal devising a new classification system for mental disorders that is informed by genetics, neuroscience, and psychology, and also takes into consideration the impact of trauma on the development of these conditions [7]. The three-way interactions between maltreatment history, MAOA genotype, and the demographic factors examined by Nikulina and colleagues accounted for 3%–5% of the variance in dysthymia symptoms [2]. Effect sizes have been greater in studies when genetic polymorphisms have been examined to account for individual differences in amygdala activation during emotion processing MRI tasks, accounting for approximately 10% of variance [8]. Clearly, however, something is still missing from the equation given the large proportion of unaccounted variance. With increasing appreciation of the role of epigenetics in disease processes [9], the incorporation of new molecular genetic approaches, together a RDoC perspective, will likely enhance risk and resilience research (See NIMH website for the RDoC project, http://www.nimh.nih.gov/research-funding/rdoc/index.shtml). What we know, Point 3: Genetic and detrimental early environment effects are not fixed Epigenetic mechanisms play a key role in the acute regulation of genes in response to changes in the environment [10]. Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in DNA nucleotide sequence, but rather alter chromatin packing and affect the likelihood of a given gene product being transcribed. As reviewed elsewhere [10], animal models of neglect suggest early adverse rearing experiences are associated with epigenetic modification of the glucocorticoid receptor gene in the hippocampus. This results in fewer glucocorticoid receptors being made. As these receptors are key in initiating the cascade of events that put the breaks on the stress response, offspring of ‘neglectful’ dams have been found to have increased stress reactivity and exhibit anxious and depression-like behaviors. Epigenetic mechanisms have also been found to mediate brain changes in ocular dominance and visual deficits associated with early monocular deprivation experiments in cats. While these vision and brain changes were originally thought to be permanent, as reviewed elsewhere [10], emerging findings suggest they can be altered by pharmacological and environmental manipulations. Neither the effects of genes, nor early adversity, are fixed. What we still need to learn The two papers in this issue have helped to close the gap in our understanding of risk and resilience in individuals maltreated as children, but there is still more to learn. The paper by Dannlowski and colleagues [1] documented associations among structural and functional brain imaging parameters and dimensional measures of child maltreatment in individuals with no lifetime history of psychiatric illness. As the authors noted, these brain changes may serve as vulnerability markers for illness. Normative data on neuroimaging measures are still lacking, however, and we do not yet have brain measures that are diagnostic and predictive of impairment and distress. Nikulina and colleagues [2] identified genetic and demographic factors that accounted for individual differences in depression and alcohol misuse symptoms, although the amount of variance accounted for was relatively small. Longitudinal follow-up studies that utilize a RDoC perspective and integrate molecular genetics and imaging approaches, together with emerging technologies to examine whole genome epigenetic markers, will likely help to further elucidate the mechanisms by which early experiences of child maltreatment confer risk for psychiatric and substance use disorders later in life.

To the Editor: We appreciate the opportunity to comment on the criticism levied by Abramowitz and colleagues about our recent paper that describes an animal model of obsessive compulsive disorder (OCD). The purpose of animal research is to recapitulate conditions in mammalian systems that are more amenable to study than the human primate, while always striving to achieve both face and construct validity (1, 2). Such validity is demonstrated by homologous (not necessarily identical) behaviors in other species that are produced by neurobiological manipulations, based on etiological theories, and possess pharmacological isomorphism to the targeted disorder. Successful demonstration of these features provides the strongest platform to investigate causal mechanisms and novel treatments. While we agree with Abramowitz et al. that it is “difficult to imagine a true animal model of this condition [OCD] (especially one involving rodents),” the reported behaviors bear striking similarities with aspects of the clinical disorder. Although the true psychological state of the animal could not be directly assessed, the observed behaviors were both evolutionarily adaptive and affected by state-evoking stimuli – much like the relationship between stress and OCD behaviors in humans (3). In our original paper, developmental exposure to the tricyclic antidepressant, clomipramine, paradoxically produced adult rats that were more anxious (determined by both elevated plus maze and marble burying), hoarded, showed more perseveration, and demonstrated problems with reversal learning and working memory. The latter two behaviors were mediated by some degree of learning impairment that delays task acquisition, which is also observed in OCD patients (4). The main argument presented by Abramowitz et al., however, is whether animals can demonstrate true compulsions “…as opposed to some other form of repetitive behavior…”. Certainly, psychiatric disorders are complex and therefore difficult to model in animals. Repetitive behavior demonstrated by OCD patients may relieve uncertainty regarding a feared consequence (5), and thus such behavior is typically related to a specific obsession that is associated with an object or a place (6). On a neurobiological level, repetitive behaviors are believed to reflect supersensitive dopamine D2 receptors in striatal brain regions, amongst other brain changes (7). Early life exposure to clomipramine increases striatal D2 receptors (8), and the present findings clearly demonstrate that these animals repeatedly check novel objects and spend more time in their presence than control subjects (Figure 1). Much like a good clinician, ruling out other causes of behavioral symptoms is important for correct diagnosis, and thus converging evidence from multiple behaviors further strengthens the possible relevance of this model. First, stereotypies, such as repeated grooming and rearing in the rats, and a behavior that is non-specific for OCD, are not present in the clomipramine rats even when provoked with a D2 agonist (unpublished observation). Second, a ‘compulsive’ behavior could result from impaired working memory, where the individual simply does not remember whether a task was completed. The repetitive behaviors observed in OCD do not reflect impaired memory recall (9), and similarly, clomipramine animals are able to choose the correct arm to enter in the delayed working memory task, but have longer response latencies than control animals. Despite these observations that clomipramine-exposed animals show state-dependent checking behaviors, delay in working memory-related tasks, and heightened anxiety in anxiety-eliciting situations, direct assessment of whether checking and delayed responding are due to an obsession in the animals is impossible. However, contrary to the assertion that “It would be nearly impossible to demonstrate whether a rat is experiencing a true obsession versus general anxiety”, these data show that clomipramine-exposed rats demonstrate behaviors that are consistent with the clinical picture. Figure 1 Compulsive checking following a single dose of the D2 agonist quinpirole. Based on the modified methods of (13), a single, acute dose of quinpirole (0.5 mg/kg) was administered. Rats were placed in an open field containing four novel objects (shaded bars), ... In response to the charge that the clomipramine model is non-specific, anxiety and OCD are often not experienced in isolation, but rather are highly comorbid with depression. Thus, the current data might further underscore their shared common neurobiology and treatment response (10). In addition, the behavioral homologies in clomipramine-exposed rats are further substantiated by selective neurochemical changes in the orbital frontal cortex (5-HT2c receptors) and the striatum (D2 receptors) – two regions and receptors that are consistently implicated in OCD (11). Rather than working to discredit models based on the impossibility of animal researchers to assess cognition through verbal report, clinicians should be working with preclinical investigators to better translate symptoms into measurable behaviors. The neurobiological underpinnings of complex disorders, including OCD, necessitate that animal models themselves need also be more complex. In our opinion, focusing on a single gene or a single behavior is overly simplistic but is necessary to understand basic mechanisms. In parallel with this endophenotype/genomic approach, animal models also need to be based on externalized, observable behaviors – much like clinicians base diagnoses on multiple symptoms that they observe – and these models ideally should also demonstrate more than one target behavior. By manipulating developmental monoamine systems that are associated with OCD and its treatment, behavioral impairment in numerous domains increases in adulthood. It is by no accident that the very treatment that reduces the aforementioned behaviors can also produce them if provided during sensitive periods of development (12). Animal research provides an important platform for understanding disorder states, their causes, and a means to test novel treatments. At this stage, current treatments for OCD have significant limitations and none of them are preventive. The greatest promise of the clomipramine model may lie in exploiting the sensitive periods for these (OCD-like) behaviors and their associated biochemistry to develop an intervention that can neurochemically re-transform aberrant circuits to a more normal trajectory. Only future testing will tell. Susan L. Andersen Britta Thompson

This is a review article that describes current data, issues, and controversies regarding long-term maintenance treatment of depression. The authors suggest that the issues represent a public health crisis. This paper will identify the need, from both a health-care and economic perspective, for more research on the efficacy of maintenance treatment for this pernicious and lifelong disorder. Data will be reviewed on the natural course of unipolar depression, focusing on clinical predictors that increase the risk of a relapse or recurrence. This review will include new data from the National Institute of Mental Health Collaborative Depression Study. Failing to achieve adequate maintenance treatment for unipolar recurrent major depression has psychopathological and psychosocial consequences, decreasing work productivity and the quality of a person's life. Published double-blind placebo-controlled studies on continuation treatment of major depression will be reviewed. The two competed double-blind placebo-controlled long-term maintenance studies of recurrent unipolar major depression will be discussed in detail. Despite the positive findings from research done to date, there remain many unresolved questions relating to the maintenance treatment of recurrent unipolar major depression, and the need for research in this area is critical. The paper concludes with recommendations for long-term maintenance treatment of unipolar major depression.

Traumatic brain injury (TBI) is associated with a host of psychiatric and neurobehavioral problems. As mortality rates have declined for severe TBI, attention has turned to the cognitive, affective, and behavioral sequelae of injuries across the severity spectrum, which are often more disabling than residual physical effects. Moderate and severe TBI can cause personality changes including impulsivity, severe irritability, affective instability, and apathy. Mild TBI, once considered a largely benign phenomenon, is now known to be associated with a range of affective symptoms, with suicidality, and with worsening or new onset of several psychiatric disorders including posttraumatic stress disorder (PTSD) and major depressive disorder. Repetitive head impacts, often in athletic contexts, are now believed to be associated with a number of emotional and behavioral sequelae. The nature and etiology of mental health manifestations of TBI (including a combination of brain dysfunction and psychological trauma and interrelationships between cognitive, affective, and physical symptoms) are complex and have been a focus of recent epidemiologic and mechanistic studies. This paper will review the epidemiology of psychiatric and neurobehavioral problems after TBI in military, civilian, and athletic contexts.

Background: The impact of maternal diet during pregnancy on child neurodevelopment is of public health and clinical relevance. We evaluated the associations of dietary quality based on the Dietary Approaches to Stop Hypertension (DASH) score and dietary inflammatory potential based on the energy-adjusted Dietary Inflammatory Index (E-DII) score during pregnancy with emotional and behavioral symptoms of offspring at 7 to 10 years of age. Methods: Individual participant data for 11,870 mother-child pairs from four European cohorts participating in the ALPHABET project were analyzed. Maternal antenatal DASH and E-DII scores were generated from self-completed food frequency questionnaires. Symptoms of depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder in children were assessed using mother-reported tests and classified within the normal or borderline/clinical ranges using validated cutoffs. Adjusted odds ratios were determined by multivariable logistic regression models and aggregated by the two-level individual participant data meta-analysis method. Results: Higher maternal DASH scores (indicating better dietary quality) were associated with lower risk of depressive and anxiety symptoms, aggressive behavior symptoms, and attention-deficit/hyperactivity disorder symptoms within the borderline/clinical ranges: odds ratio [OR] 0.97, 95% confidence interval [CI], 0.95-0.99; OR 0.97, 95% CI, 0.94-0.99; OR 0.97, 95% CI, 0.95-0.98, per one-unit DASH score increase, respectively. For depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder symptoms, a one-unit increase in E-DII scores (a more proinflammatory diet) was associated with a 7% increased risk of all three analyzed emotional and behavioral symptoms: OR 1.07, 95% CI, 1.03-1.11; OR 1.07, 95% CI, 1.02-1.13; OR 1.07, 95% CI, 1.01-1.13, respectively. Conclusions: Our findings suggest that a maternal low-quality and proinflammatory diet may increase the risk of emotional and behavioral symptoms in children. This work was supported by an award from the European Union’s Horizon 2020 research and innovation programme under the ERA-Net Cofund of the Joint Programming Initiative Healthy Diet for Healthy Life (JPI-HDHL) (http://www.healthydietforhealthylife.eu) action number 696295 (Biomarkers for Nutrition and Health). Cofunding was provided by Science Foundation Ireland, Ireland (Grant No. SFI/16/ERA-HDHL/3360 [to CMP]), the UK Biotechnology and Biological Sciences Research Council (ERA-HDHL Biomarkers: BBSRC BB/P028187/1 [to CR]), the Polish National Centre for Research and Development (ERA-HDHL/01/ALPHABET/1/2017 [to KP]), the ZonMw The Netherlands (Grant No. 529051014; 2017) ALPHABET project (Grant No. 696295; 2017 [to LD]) and the French National Agency of Research (reference AnrR16227KK [to BH]). ALSPAC: This work was supported by the UK Medical Research Council and Wellcome (Grant No. 102215/2/13/2) and the University of Bristol. This publication is the work of the authors and Matthew Suderman will serve as guarantors for the contents of this paper. EDEN: This work was supported by the Foundation for Medical Research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR Cohorte Santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale, a complementary health insurance (MGEN), French National Agency for Food Security, French-speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM). Generation R: This work was supported by the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. Dr Liesbeth Duijts received funding from the European Union's Horizon 2020 cofunded programme ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL) (ALPHABET project (Grant No. 696295; 2017), ZonMW The Netherlands (Grant No. 529051014; 2017). Dr. Hanan El Marroun was supported by Stichting Volksbond Rotterdam, the Dutch Brain Foundation (De Hersenstichting, project number GH2016.2.01), and NARSAD Young Investigator Grant No. 27853 from the Brain & Behavior Research Foundation. The project received funding from the European Union’s Horizon 2020 Research and Innovation Programme (LIFECYCLE project, Grant No. 733206; 2016). REPRO_PL: This work was supported by the Ministry of Science and Higher Education, Poland (PBZ-MEiN-/8/2//2006; Contract No. K140/P01/2007/1.3.1.1); by the grant PNRF-218-AI-1/07 from Norway through the Norwegian Financial Mechanism within the Polish-Norwegian Research Fund, National Science Centre under the call of JPI HDHL Nutrition and Cognitive Function (2015/17/Z/NZ7/04273), and the National Science Centre, Poland (DEC-2014/15/B/NZ7/00998). Mònica Guxens (CPII18/00018) and Maribel Casas (CP16/00128) are funded by a Miguel Servet fellowship (from the Spanish Institute of Health Carlos III). We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Programme.

This paper proposes a heuristic framework for an Addictions Neuroclinical Assessment (ANA) that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (AD) are presently diagnosed, and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated. In addition, recent changes in the nosology of AD, challenges to current classification systems, and prior attempts to subtype individuals with AD are described. Complementary initiatives, including the Research Domain Criteria (RDoC) project, which have established frameworks for the neuroscience of psychiatric disorders, are discussed. Three domains, executive function, incentive salience, and negative emotionality, tied to different phases in the cycle of addiction, form the core functional elements of AD. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of AD on the basis of process and etiology, an advance that can lead to improved prevention and treatment.