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The Neurobiology of Bipolar Disorder
Abstract
The neurobiology of bipolar disorder is reviewed. Bipolar disorder is associated with alterations in central nervous system (CNS) function from the level of large-scale brain circuits to intracellular signal transduction mechanisms. Because of the broad spectrum over which these abnormalities appear, the causative effects are most likely present in the lowest common denominator of all of these systems. Current evidence points to subtle alterations in signal transduction that reverberate downstream both intra- and extracellularly to produce the symptoms of bipolar disorder.
... Increasing evidence also implicates abnormal protein kinase C (PKC) activity and distribution in the etiology of BD [20][21][22]. Biochemical data support changes in PKC and its substrates [23,24], and an altered PKC signaling pathway after treatment with mood stabilizers [23,25] in BD patients. Preclinical findings also support that alterations in PKC and its substrates are induced by amphetamine [26] or sleep deprivation [27]. ...
... The PSD paradigm is highly relevant to understanding the etiology of BD, since alterations in sleep-wake patterns profoundly affect patients suffering from this disorder. Indeed, the manic phase is characterized by a marked decrease in the need for sleep [20]. Accordingly, the PSD model has proven valuable in the testing of potential antimanic drugs, and in the examination of neurobiological correlates between manic reactions and sleep loss, thus providing a useful tool in gaining further knowledge and a better understanding of the pathophysiology of BD. ...
... The possible involvement of PKC signaling in the pathophysiology of BD may have relevant clinical implications, since many patients are unresponsive to standard pharmacological monotherapies [4,20]. In fact, there is increasing evidence indicating that optimal response by most BD patients requires multiple-drug therapy [20], supporting the strategy of adding a second agent rather than switching to a different monotherapy [6]. ...
Previous studies have suggested that manic states and sleep deprivation could contribute to the pathophysiology of bipolar disorder (BD) through protein kinase C (PKC) signaling abnormalities. Moreover, adjunctive therapy has become a standard strategy in the management of BD patients who respond poorly to current pharmacological treatments.
Thus, the aim of this study was to investigate the possible involvement of PKC inhibition by tamoxifen both separately or in combination with lithium, in paradoxical sleep deprivation (PSD)-induced hyperactivity, one facet of mania-like behavior.
Adult male C57BL/6J mice were randomly distributed (n = 7/group) in 24-h PSD or control groups and injected intraperitoneally (i.p.) with vehicle, lithium (50, 100, or 150 mg/kg) or tamoxifen (0.5, 1.0, or 2.0 mg/kg - experiment 1). In a second experiment, mice were injected i.p. with vehicle or a combination of subeffective doses of lithium and tamoxifen. Animals were subjected to a protocol based on repetitive PSD conditions, followed by assessment of locomotion activity in the open-field task.
PSD significantly increased locomotor activity in both experiments. These behavioral changes were prevented by a treatment with lithium or tamoxifen, or a combined treatment with both lithium and tamoxifen.
Therefore, our findings suggest that lithium and tamoxifen exert reversal effects against PSD-induced hyperactivity in mice.
Furthermore, tamoxifen as an adjunct to lithium therapy provides support for an alternative treatment of individuals who either do not respond adequately or cannot tolerate the adverse effects associated with therapeutic doses of lithium.
... S.D. has been associated with a variety of neurodegenerative and behavioural disorders. Diminished sleep can be a positive trigger for manic episodes (Berns et al. 2003). Numerous neurotransmitter systems have been linked to behavioural changes, including dopamine (DA), serotonin (5-HT), and norepinephrine (N.E.). ...
... Norepinephrine (N.E.) has long been associated with depression and manic episodes (Decker et al. 2000;Machado et al. 2004). Glutamate is the most important excitatory neurotransmitter (Seigel et al. 1984;Berns et al. 2003;Armani et al. 2012). Glutamate has a deleterious impact on brain physiology in circumstances of overexcitation (Tamilselvan et al. 2017). ...
Sleep deprivation disrupts most neurotransmitters, which can lead to adverse behavioural changes and other psychiatric illnesses. Many neurotransmitter systems, including dopamine (DA), serotonin (5-HT), norepinephrine (N.E.) and GABA, have been implicated in the pathophysiology of mood disorders. The precise significance of sleep deprivation (S.D.) changes in the neurotransmitter levels and the mechanism underlying behavioural alterations is unknown. According to research, sleep deprivation (S.D.) has a major effect on an individual's quality of life and ability to perform essential physiological functions. As a result, we wanted to confirm the levels of neurotransmitters and behavioural modifications in zebrafish after 24, 48, and 72 hours of sleep deprivation and glutamate treatment on the sleep-deprived groups. The T-maze test was used to assess learning and memory alterations in zebrafish. We used the Novel Tank Test (NTT) and Light and Dark Test (LDT) to examine the anxiety-like behaviour. The spectrofluorimetric method was used to determine the quantities of DA, 5-HT, N.E. and GABA. From this study, it is evident that 72h sleep-deprived fish had a loss of learning and memory via T-maze test and also the anxiety levels were very high in the sleep-deprived group than the other groups. The groups that received glutamate after sleep deprivation showed betterment in the behavioural response. Also, the levels of neurotransmitters were increased in the glutamate treated groups than the sleep-deprived groups. Our findings indicate that sleep loss dramatically impairs behavioural responses and disrupts most neurotransmitter concentrations. When sleep-deprived fish were given glutamate, their behaviour and neurotransmitter levels were nearly identical to those of the control group. This study will have a greater impact on sleep deprivation therapy and pave the way for using the neurotransmitters as external therapeutic agents in treating sleep deprivation and other behavioural changes related to sleep deprivation.It has been suggested that zebrafish is an excellent testing subject for loss of sleep on cognition and that it may also be an efficient model for unravelling the pathways that underpin learning and memory formation.
... [70][71][72] There is an increasing amount of data showing that sleep loss is associated with HPA axis alterations, activation of inflammatory parameters and increases in oxidative stress parameters in humans and in animal models. 39,59,73,74 Indeed, the present study showed that HPA axis alterations and oxi- with BD are also related to the elevation of IL-6. 74 Therefore, together, these studies suggest that sleep deprivation and mania-like behaviors are associated with inflammatory system alteration. ...
... Therefore, PSD may be considered an important tool for the elucidation of the physiopathology and etiology of BD.38 In the present study, the mania-like behavior induced by PSD was accompanied by increases in the circulating levels of corticosterone and ACTH, which indicates that this model of PSD activates the HPA axis. In agreement with the present findings, a recent study demonstrated an elevated corticosterone concentration in the serum of PSD rats when compared to controls.39 In addition, and corroborating the findings of the present study, several studies have demonstrated that the levels of corticosterone are increased after PSD.[40][41][42][43] Suchecki and colleagues 40 showed that PSD induced using different methods increased ACTH and corticosterone secretion. ...
OBJECTIVES:
The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD).
METHODS:
Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels.
RESULTS:
The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD.
CONCLUSIONS:
Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system - alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers.
... The neurobiology of bipolar disorder is 28 complex and poorly understood, with evidence supporting abnormalities of structure and/or 29 function at many levels of the nervous system (Davidson et al., 2002; Goldbeter, 2011; Huber 30 et al., 2000; Sanacora et al., 2012). One of the strongest domains of evidence relates toBerns and Nemeroff, 2003; Davidson et al., 2002; Goldbeter, 2011; Murray and Harvey, 35 2010; Pavuluri et al., 2005; Sanacora et al., 2012; Schloesser et al., 2012). ...
... Antidepressant medications can induce 'manic switching' in a proportion of depressed 311 patients (Damluji and Ferguson, 1988; Schloesser et al., 2012). In the proposed model, theBenes and Berretta, 2001; Berns and Nemeroff, 2003; Davidson et al., 2002; Goldbeter, 332 2011; López-Muñoz et al., 2006; Tretter et al., 2011). Here, manic and depressive episodes the real part represents the fluctuations around a depressive background, and the imaginary part symbolizes the variations around a manic substrate. ...
Bipolar disorder is characterized by repeated erratic episodes of mania and depression, which can be understood as pathological complex system behavior involving cognitive, affective and psychomotor disturbance. In order to illuminate dynamical aspects of the longitudinal course of the illness, we propose here a novel complex model based on the notion of competition between recurrent maps, which mathematically represent the dynamics of activation in excitatory (Glutamatergic) and inhibitory (GABAergic) pathways. We assume that manic and depressive states can be considered stable sub attractors of a dynamical system through which the mood trajectory moves. The model provides a theoretical framework which can account for a number of complex phenomena of bipolar disorder, including intermittent transition between the two poles of the disorder, rapid and ultra-rapid cycling of episodes and manicogenic effects of antidepressants.
Copyright © 2015. Published by Elsevier Ltd.
... According to physiological studies, neuroplastic variations may be the underlying mechanism which explain the misregulation of the main circuits involved in the emotional processing (Kandel et al., 2000;Berns and Nemeroff, 2003). This emotional dysregulation is somatically represented as irregular mood swings. ...
... This emotional dysregulation is somatically represented as irregular mood swings. Therefore, we believe that the clinical course of bipolar disorder, which is characterized by repeated erratic cycles of mania, depression and episodes of randomly appeared chaotic transitional states (Gottschalk et al., 1995;Berns and Nemeroff, 2003;Rabinovich et al., 2012), may also be understood based on the concept of chaotic intermittency. Manic, depressive and transitional states could be considered as stable or unstable attractors (Tretter et al., 2011). of a dynamical system through which the mood trajectory moves. ...
The brain presents a large number of spatially connected and interacting neurons and synapses that form many positive and negative feedback circuits. These complex networks in interaction with the environment have been experimentally demonstrated to produce temporally chaotic behavior which may be detected in recordings from individual nerve cells or neural ensembles (Korn and Faure, 2003). According to such paradigm, the brain could be considered as a complex system with chaos as its predominant dynamics. As a result, concepts of complex system and chaos theory could be applied to the studies of normal and abnormal brain functions.
... Bipolar disease exhibits overlaps in genetic susceptibility with schizophrenia and associated disorders and is characterized by profound changes in circadian rhythms and by neural circuit instability and enhanced sensitivity to minor environmental and homeostatic cues indicative of a chaotic system (Berns and Nemeroff, 2003;Newberg et al., 2008;Schloesser et al., 2008). Risk genes for bipolar disease include a host of receptor genes for serotonin, dopamine and GABA neurotransmission, glutamate signaling pathways, circadian rhythms and direct targets of front-line therapeutic agents, namely lithium and valproate (Berns and Nemeroff, 2003;Newberg et al., 2008;Schloesser et al., 2008). ...
... Bipolar disease exhibits overlaps in genetic susceptibility with schizophrenia and associated disorders and is characterized by profound changes in circadian rhythms and by neural circuit instability and enhanced sensitivity to minor environmental and homeostatic cues indicative of a chaotic system (Berns and Nemeroff, 2003;Newberg et al., 2008;Schloesser et al., 2008). Risk genes for bipolar disease include a host of receptor genes for serotonin, dopamine and GABA neurotransmission, glutamate signaling pathways, circadian rhythms and direct targets of front-line therapeutic agents, namely lithium and valproate (Berns and Nemeroff, 2003;Newberg et al., 2008;Schloesser et al., 2008). These therapeutic agents are synergistic in regulating the development and deployment of signaling pathways mediating state transitions associated with dynamic genome-wide alterations in transcriptional regulation, histone code modifications and chromatin remodeling, neural development, synaptic function and plasticity, neuroprotection and circadian rhythms (Leng et al., 2008;Newberg et al., 2008;Schloesser et al., 2008). ...
Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified not only by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene–environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity.
... Bipolar disorder is associated with structural, functional and physiological alterations in the brain of bipolar patients, which reflect chemical, neurochemical and metabolic changes, specifically at the levels of brain metabolites and neurotransmitters, as already detected by different techniques (Silverstone et al., 2005). Abnormalities in signal transduction pathways, in particular G proteins, adenylate cyclase (AC) and phosphatidylinositol (PI) signalling cascade, as well as protein kinase C (PKC) were related with the pathophysiology of bipolar disorder (Berns & Nemeroff, 2003, Brunello & Tascedda, 2003 Manji et al., 2001; Manji & Lenox, 2000a, 2000b). Despite the widespread clinical use of lithium salts, the pharmacological mode of action underlying Li + mood stabilizing effects is still unclear and several hypotheses have been advanced. ...
... Overall, these results demonstrate that intracellular cAMP levels regulate Li + uptake in a Ca 2+ -dependent manner, and Li + plays an important role in the homeostasis of this second messenger in neuronal cells. This is relevant data to understand the mechanism of action of Li + , taking into account several aspects already mentioned in the literature such as: bipolar disorder is associated with deregulation in AC mediated signal transduction processes, which are affected by Li + (Berns & Nemeroff, 2003; Brunello & Tascedda, 2003; Manji & Lenox, 2000a, 2000b Manji et al., 2001), and with increased [Ca 2+ ] i (Hough et al., 1999) pointing to an interaction between intracellular signalling mechanisms mediated by Ca 2+ and cAMP (Cooper et al., 1995); bipolar patients with a [Ca 2+ ] i higher than normal respond better to Li + treatment, indicating a possible correlation between Ca 2+ levels and Li + response (Ikeda & Kato, 2003). ...
... Finally, neuroimaging evidence highlighted several structural alterations in frontal regions, hippocampus, amygdala and corticolimbic network, including decrease of volume and disruption in anatomical connections (Kloiber et al., 2020). The neurobiological alterations in BD are coupled to impairments in specific cognitive domains related to language, attention, working memory, visual processes and emotional codification (Berns and Nemeroff, 2003). ...
Background:
The recent widespread use of diffusion tensor imaging (DTI) tractography allowed researchers to investigate the diffusivity modifications and neuroanatomical changes of white matter (WM) fascicles in major psychiatric disorders, including bipolar disorder (BD). In BD, corpus callosum (CC) seems to have a crucial role in explaining the pathophysiology and cognitive impairment of this psychiatric disorder. This review aims to provide an overview on the latest results emerging from studies that investigated neuroanatomical changes of CC in BD using DTI tractography.
Methods:
Bibliographic research was conducted on PubMed, Scopus and Web of Science datasets until March 2022. Ten studies fulfilled our inclusion criteria.
Results:
From the reviewed DTI tractography studies a significant decrease of fractional anisotropy (FA) emerged in the genu, body and splenium of CC of BD patients compared to controls. This finding is coupled with reduction of fiber density and modification in fiber tract length. Finally, an increase of radial (RD) and mean diffusivity (MD) in forceps minor and in the entire CC was also reported.
Limitations:
Small sample size, heterogeneity in terms of methodological (diffusion gradient) and clinical (lifetime comorbidity, BD status, pharmacological treatments) characteristics.
Conclusions:
Overall, these findings suggest the presence of structural modifications in CC in BD patients, which may in turn explain the cognitive impairments often observed in this psychiatric disorder, especially in executive processing, motor control and visual memory. Finally, structural modifications may suggest an impairment in the amount of functional information and a morphological impact within those brain regions connected by CC.
... All of these factors make REMSD an effective animal model for identifying novel treatment targets. Additionally, abnormalities in the circadian cycle are observed in BD patients, particularly during the manic period, making REMSD a crucial tool in studying the genesis of the disease [26]. Our findings show that REMSD significantly increased hyperactivity and decreased hypoactivity immediately after the sleep deprivation. ...
Bipolar disorder is one of the most common psychiatric illnesses with cyclic changes in mood from mania or hypomania to depression or vice versa. In bipolar disorder cognitive and behavioral abilities of patients are affected. Sleep abnormalities are frequently associated with BD. Preservation of stable sleep cycles is therefore a key to the maintenance of stability in BD, indicating the crucial role of circadian rhythms in this disorder. Changes in the behaviour is the main cause of BD. Many mood stabilizers are used to treat this disorder. Many animal models are used to study the pathophysiology, pharmacology and treatment strategy of BD. Sleep plays an important role in the development and progression of bipolar disorder. A further episode of bipolar disorder is also decided by the quality and duration of sleep. REM sleep deprived animals develop mania like behavior and used as a best model to study the factors involved in development if this diseases. Light, both dark and bright regulates circadian rhythm which play a crucial role in behaviour of the animal. With this background, we wish to understand the behavioral consequences of bright light therapy in REM sleep deprived animals and to know whether they play any direct role or will be an additional treatment strategy with mood stabilizer like lithium.
... In fact, the manic phase of this disorder is characterized by a distinct reduction in the need for sleep. 32 Also in the present study, the mice were sacrificed on the seventh day after the behavioural tests, and the brains extracted for histological studies. Hematoxylin and Eosin (H&E) staining of the striatum revealed that sleep deprivation increased the extent of striatum neuronal damage and subsequently decreased the population of viable neurons in mice brains. ...
Background: Sleep deprivation has often been implicated in several neurological disorders. Centella lujica is a psychoactive herb with medically-beneficial therapeutic potential. The current study sought to evaluate the neuroprotective effect of Centella lujica supplement in experimental animals.Methods: Sleep deprivation in mice was done using the multiple platforms over water model.Results: Upon treatment with Centella lujica supplement, the parameters of anxiety-like behaviour induced by sleep deprivation were found to be significantly diminished in comparison to the sleep deprived animals.Conclusions: Centella lujica treatment significantly decreased hyper locomotion, and anxiety-like behaviour caused by sleep deprivation.
... Since the development of functional neuroimaging, researchers have looked to identify the brain structures and neurocognitive processes that underpin BD. However, despite significant advancements in imaging technology, studies have revealed that the biology of the brain in BD is Early intervention in bipolar disorders: Setting the stage from mechanisms to models deeply complex and that episodes of mania and depression produce widespread changes in the brain, rather than simply affecting particular regions [44]. Nevertheless, such research has identified significant differences in the brain structures of people with BD compared to healthy controls. ...
The concept of early intervention for bipolar disorder (BD) is both attractive and logical as there is often a considerable delay between the onset of BD symptoms and diagnosis. This chapter addresses key definitional and conceptual considerations for early intervention in BD and exposes the expansive gaps in our knowledge of the phenomenology of BD, prognostication, and disease progression and trajectory. These gaps highlight that early intervention for BD—in terms of treatment specificity and timing—is far from being realised. There are though significant risks associated with implementing early intervention strategies at this stage, which may range from unnecessarily prescribing potentially harmful medication to perhaps inadvertently accelerating the progression of the illness. Until there are major scientific and clinical advancements, this chapter provides a conservative yet involved approach for early intervention in BD.
... [37] Mood stabilizer precise stabilizer of anticonvulsant proves prophylactic for manic depressive illness in instance to sodium valproate due to lack of sedative drugs [38] , psychosocial risk factors contribute onset, course or BD expression which supportive social and non-supportive interaction may occurs due to environmental features, includes cognitive behavioral therapy. [39] BD verifies that effective concern and analysis with proper findings may generalized with psychiatric disorders may suggest appropriate treatment for a chronic disorder and chronic self management that found to be creativity of concerned patients may generate self management solution to discernment in BD population. ...
Bipolar disorder persistent undiagnosed complex with diverse
appearance which provides psychological healing with
pharmacotherapy diminishes frequency, severity, manic and depressive
episodes. Bipolar disorder targets on comorbid conditions such as
panic, anxiety, and abuse, personality disorder evaluated in
psychosocial risks for unipolar depression. We conclude that
combination of variant therapies, age onset, genetic factors are
influenced by cognitive behavioral therapies may help to cure bipolar
disorder.
... Taken together, these circumstances characterize REMSD as a useful animal model to find new therapeutic targets. Furthermore, REMSD is an important method in the understanding of the etiology of BD, because changes in circadian cycle are noticed in BD patients, mainly in the manic phase [36]. From our data, REMSD significantly increased central, peripheral and rearing activities in OFT. ...
A number of neurotransmitter systems have been implicated in contributing to the pathology of mood disorders, including those of dopamine (DA), serotonin (5-HT), norepinephrine (NE) and γ-aminobutyric acid (GABA). Rapid eye movement sleep deprivation (REMSD) alters most of the neurotransmitters, which may have adverse behavioural changes and other health consequences like mania and other psychiatric disorders. The exact role of REMSD altered neurotransmitter levels and the manner in which emerging consequences lead to mania-like behaviour is poorly understood. Thus, we sought to verify the levels of neurotransmitter changes after 48, 72 and 96 h of REMSD induced mania-like behaviour in mice. We performed modified multiple platform (MMP) method of depriving the REM sleep and one group maintained as a control. To measure the hyperactivity through locomotion, exploration and behavioural despair, we performed the Open Field Test (OFT) and the Forced Swim Test (FST). Quantitative determinations of DA, 5-HT, NE and GABA concentrations in four distinct brain regions (cerebral cortex, hippocampus, midbrain, and pons) were determined by the spectrofluorimetric method. These experiments showed higher locomotion and increased swimming, struggling/climbing and decreased mobility among REMSD animals as well as disrupted concentrations of the majority of the studied neurotransmitters during REMSD. Our study indicated that REMSD results in mania-like behaviour in mice and associated disruption to neurotransmitter levels, although the exact mechanisms by which these take place remain to be determined.
... To this end, functional/ neurophysiological phenotypes may be more appropriate than structural deficits since dysfunction often occurs without apparent changes in structure. Accumulating evidence suggests that mental disorders such as Alzheimer's disease, schizophrenia, or autism but also depression and bipolar disorders can arise from abnormal intrinsic activity in specific brain circuits in the absence of detectable structural lesions (26,(111)(112)(113)(114). In autism research clinical investigators stress the need for functional longitudinal studies of the brain (functional magnetic resonance imaging, fMRI) in human infants, toddlers and children at high age resolution in order to define the ontogeny of the disease (15). ...
Autism is a severe neurodevelopmental disorder which affects information processing in the brain as the result of an abnormally developed cortex, brought about in ways that are poorly understood. The disorder is characterized by a very early onset, however, neurobiological studies at such young ages are often precluded in humans, thus, rendering respective research in appropriate animal models of the disease invaluable. The bulk of this research has focused mainly on how experimental models differ from normal rather than on when they begin to differ. However, understanding the neurobiology of autism at its onset is important for both describing and treating the disorder. Moreover, modelling human behaviours in animals is often very difficult. Therefore, in order for neurobiological research of autism to proceed it is essential to "decompose" the disorder into simpler, behavior-independent biological parameters. Here, I propose how network dynamics of local microcircuits may serve such a role in order to derive developmental trajectories of the cerebral cortex that will allow us to detect and investigate the disorder at its very beginning.
... Estimates of the prevalence of bipolar I disorder have ranged from 0.8% to 1.6% of the general population ( Berns and Nemeroff, 2003). Although the genetic participation is well established, the identification of genes has remained elusive. ...
Background:
Bipolar disorder type I (BPI) affects approximately 1% of the world population. Although genetic influences on bipolar disorder are well established, identification of genes that predispose to the illness has been difficult. Most genetic studies are based on categorical diagnosis. One strategy to overcome this obstacle is the use of quantitative endophenotypes, as has been done for other medical disorders.
Methods:
We studied 619 individuals, 568 participants from 61 extended families and 51 unrelated healthy controls. The sample was 55% female and had a mean age of 43.25 (SD 13.90; range 18-78). Heritability and genetic correlation of the trait scale from the Anxiety State and Trait Inventory (STAI) was computed by using the general linear model (SOLAR package software).
Results:
we observed that anxiety trait meets the following criteria for an endophenotype of bipolar disorder type I (BPI): 1) association with BPI (individuals with BPI showed the highest trait score (F = 15.20 [5,24], p = 0.009), 2) state-independence confirmed after conducting a test-retest in 321 subjects, 3) co-segregation within families 4) heritability of 0.70 (SE: 0.060), p = 2.33 × 10(-14) and 5) genetic correlation with BPI was 0.20, (SE = 0.17, p = 3.12 × 10(-5)).
Limitations:
Confounding factors such as comorbid disorders and pharmacological treatment could affect the clinical relationship between BPI and anxiety trait. Further research is needed to evaluate if anxiety traits are specially related to BPI in comparison with other traits such as anger, attention or response inhibition deficit, pathological impulsivity or low self-directedness.
Conclusions:
Anxiety trait is a heritable phenotype that follows a normal distribution when measured not only in subjects with BPI but also in unrelated healthy controls. It could be used as an endophenotype in BPI for the identification of genomic regions with susceptibility genes for this disorder.
... From a more biologically plausible perspective, as previously hypothesized in Hadaeghi et al. (2015), an underlying winnerless competition between the excitatory and inhibitory pathways may dynamically determine the variation of the excitatory and inhibitory parameters of Equation (1). Studies using a variety of methods suggest that pathological competition between the electrical activity generated by the excitatory (glutamatergic) and inhibitory (GABAergic) neural circuits may explain the bi-stability and erratic time-course of bipolar disorder (Benes & Berretta, 2001;Berns & Nemeroff, 2003;Davidson et al., 2002;Duman, 2002;Montague et al., 2012;Tretter et al., 2011). To mathematically represent the competition, our chaotic model is further grounded in the dynamics of electrical activity in coupled neuronal excitatory and inhibitory circuits. ...
Bipolar disorder is characterized by repeated episodes of mania and depression, and can be understood as pathological complex system behaviour involving cognitive, affective and psychomotor disturbance. Accurate prediction of episode transitions in the long-term pattern of mood changes in bipolar disorder could improve the management of the disorder by providing an objective early warning of relapse. In particular, circadian activity changes measured via actigraphy may contain clinically relevant signals of imminent systemic dysregulation. In this study, we propose a mathematical index to investigate the correlation between apparently irregular circadian activity rhythms and critical transitions in episodes of bipolar disorder. Not only does the proposed index illuminate the effects of pharmacological and psychological therapies in control over the state, but it also provides a framework to understand the dynamic (or state-dependent) control strategies. Modelling analyses using our new approach suggest that key clinical goals are minimizing side effects of mood stabilizers as well as increasing the efficiency of other therapeutic strategies. ARTICLE HISTORY
... From a more biologically plausible perspective, as previously hypothesized in Hadaeghi et al. (2015), an underlying winnerless competition between the excitatory and inhibitory pathways may dynamically determine the variation of the excitatory and inhibitory parameters of Equation (1). Studies using a variety of methods suggest that pathological competition between the electrical activity generated by the excitatory (glutamatergic) and inhibitory (GABAergic) neural circuits may explain the bi-stability and erratic time-course of bipolar disorder (Benes & Berretta, 2001;Berns & Nemeroff, 2003;Davidson et al., 2002;Duman, 2002;Montague et al., 2012;Tretter et al., 2011). To mathematically represent the competition, our chaotic model is further grounded in the dynamics of electrical activity in coupled neuronal excitatory and inhibitory circuits. ...
Bipolar disorder is characterized by repeated episodes of mania and depression, and can be understood as pathological complex system behavior involving cognitive, affective and psychomotor disturbance. Accurate prediction of episode transitions in the long term pattern of mood changes in bipolar disorder could improve management of the disorder by providing an objective early warning of relapse. In particular, circadian activity changes measured via actigraphy may contain clinically relevant signals of imminent systemic dysregulation. In this study, we propose a mathematical index to investigate the correlation between apparently irregular circadian activity rhythms and critical transitions in episodes of bipolar disorder. Not only does the proposed index illuminate the effects of pharmacological and psychological therapies in control over the state, but it also provides a framework to understand the dynamic (or state dependent) control strategies. Modelling analyses using our new approach suggests that key clinical goals are minimizing side effects of mood stabilizers as well as increasing the efficiency of other therapeutic strategies.
... In BD patients, even though they may show cognitive impairment in premorbid states, these impairments may not necessarily be mirrored in poor premorbid functioning as defined by the PAS. This is in accordance with the notion that BD may represent a perturbation in regulatory systems that is not expressed until a later stage of development [67]. ...
Introduction: This study aimed to describe the differences in global functioning in BD type I and type II patients with high premorbid functioning.
Methods: From a more extensive sample of 140 subjects, fifty euthymic bipolar outpatients with high level of premorbid social functioning measured by Premorbid Adjustment Scale were enrolled. 90 BD were excluded because they had a low premorbid social functioning. Current social and neuropsychological functioning was assessed.
Results: Cluster analysis showed that some BD patients maintain a high functioning, while other patients suffer of a loss of global functioning. Multivariate analysis showed that a lower social functioning, independently from premorbid social functioning, can be associated with a loss of executive
functions (p = .009). In this analysis the effects of bipolar type (I or II), age at onset, current social roles and duration of illness were absent or not significant (p > .05).
Discussions: This is the first study to distinguish levels of global functioning in euthymic BD patients that had the same premorbid social functioning. These important differences in the course of the BD can be assessed through psychosocial and neuropsychological assessment tools for a more appropriate
management of the variables able to modify the course of disorder, also in euthymic phase. This practice becomes crucial in the definition and implementation of specific psychosocial treatments in the short and long-term course of disease, providing a new and specific area of intervention for bipolar disorder: the cognition
... 8,9 Further, it has quite consistently been reported that bipolar depressive episodes show a statistical tendency to be briefer in duration than unipolar ones. 10-15 Bipolar depression tends to be atypical, with prominent fatigue, hypersomnia, and reverse diurnal mood variability, 16 as well as higher rates of psychomotor retardation, difficulty thinking, early morning awakening, morning worsening, and psychotic features. 17 Compared to unipolar depression, bipolar disorder is related to an earlier age of onset and a more rapid recurrence. ...
Research on deep brain stimulation (DBS) for treatment-resistant psychiatric disorders has established preliminary efficacy signals for treatment-resistant depression. There are only few studies on DBS that included patients suffering from bipolar disorder. This article gives an overview of these studies concerning DBS targets, antidepressant efficacy, and the occurrence of manic/hypomanic symptoms under stimulation. First, promising results show that all patients experienced significant improvement in depressive symptomatology. In a single case, hypomanic symptoms occurred, but they could be resolved by adjusting stimulation parameters. Furthermore, this article highlights important clinical differences between unipolar and bipolar depression that have to be considered throughout the course of treatment.
... The brain basis of bipolar disorder is complex, involving multiple pathways. A range of research suggests that pathological competition between electrical activity generated by excitatory (glutamatergic) and inhibitory (GABAergic) frontal circuits is a key pathogenic pathway to bipolar disorder (Benes and Berretta, 2001;Berns and Nemeroff, 2003;Davidson et al., 2002;Duman, 2002;Montague et al., 2012;Tretter et al., 2011). Similarly, there is growing consensus from neuroimaging research that bipolar disorder involves impaired connectivity between the frontal cortex and lower brain regions involved in emotion processing (Baghdadi et al., 2015;Davidson et al., 2002;McKenna et al., 2014;McKenna and Eyler, 2012). ...
Importance:
In the absence of a comprehensive neural model to explain the underlying mechanisms of disturbed circadian function in bipolar disorder, mathematical modeling is a helpful tool. Here, circadian activity as a response to exogenous daily cycles is proposed to be the product of interactions between neuronal networks in cortical (cognitive processing) and subcortical (pacemaker) areas of the brain.
Objective:
To investigate the dynamical aspects of the link between disturbed circadian activity rhythms and abnormalities of neurotransmitter functioning in frontal areas of the brain, we developed a novel mathematical model of a chaotic system which represents fluctuations in circadian activity in bipolar disorder as changes in the model's parameters.
Design, setting and participants:
A novel map-based chaotic system was developed to capture disturbances in circadian activity across the two extreme mood states of bipolar disorder. The model uses chaos theory to characterize interplay between neurotransmitter functions and rhythm generation; it aims to illuminate key activity phenomenology in bipolar disorder, including prolonged sleep intervals, decreased total activity and attenuated amplitude of the diurnal activity rhythm. To test our new cortical-circadian mathematical model of bipolar disorder, we utilized previously collected locomotor activity data recorded from normal subjects and bipolar patients by wrist-worn actigraphs.
Results:
All control parameters in the proposed model have an important role in replicating the different aspects of circadian activity rhythm generation in the brain. The model can successfully replicate deviations in sleep/wake time intervals corresponding to manic and depressive episodes of bipolar disorder, in which one of the excitatory or inhibitory pathways is abnormally dominant.
Conclusions and relevance:
Although neuroimaging research has strongly implicated a reciprocal interaction between cortical and subcortical regions as pathogenic in bipolar disorder, this is the first model to mathematically represent this multilevel explanation of the phenomena of bipolar disorder.
... Furthermore, dysfunctional GSK-3b has also been found to be involved in major depression (13). This Research Article involvement could be linked to the deficient serotonergic neurotransmission observed in depression (14), considering that serotonergic activity contributes to the inhibitory control of GSK-3b in mammalian brain in vivo (15). This conclusion is based on the finding that serotonin (5-HT) itself, as well as fluoxetine (a selective serotonin re-uptake inhibitor) and 5-HT 1A agonists, augments serine 9 phosphorylation with the consequent inhibition of GSK-3b (15). ...
Novel pyrimidin-4-one derivatives have been synthesized using EDC coupling and evaluated as glycogen synthase kinase-3β (GSK-3β) inhibitors. Among all the synthesized compounds, compound 5 (3-methyl-6-phenyl-2-(piperazin-1-yl)-3,4-dihydropyrimidin-4-one) exhibited the most potent inhibitory activity against GSK-3β with IC50 value of 74 nM. The molecular docking studies were performed to elucidate the binding modes of the compounds with the target and a crucial interaction involving hydrogen bond formation with Val-135 to the active site of GSK-3β was observed. Furthermore the synthesized compounds were subjected to in vivo evaluation of their antidepressant activity and compound 5 showing highest inhibition of GSK-3β was also found to significantly reduce the duration of immobility at 50mg/Kg, when compared with fluoxetine, a known antidepressant drug. The results of our study suggest that compound 5 may serve as a valuable template for the design and development of inhibitors of GSK-3β with antidepressant activity. This article is protected by copyright. All rights reserved.
... Moreover, our limited knowledge into the workings of a healthy brain have only complicated efforts to understand the pathophysiological changes in patients with bipolar disorder; an understanding that requires linking the complex behavioral manifestations, functional deficits and the cyclic nature of the disorder with it's neurochemical, neurobiological, and genetic underpinnings [19]. Several studies have suggested that there are differences between BPD patients and healthy controls in many areas, as well as some differences between BPD patients and patients with MDD. ...
There have been many studies that have examined various aspects of the pathophysiology of bipolar disorder, with many positive findings in several areas of neuroimaging and metabolic abnormality. These studies might allow some conclusions to be drawn about the underlying pathophysiology. Additionally, it is of significant interest to determine if there are pathophysiological differences between patients with bipolar disorder type I (BPD-I) and those with bipolar disorder type II (BPD-II). The present review examines imaging studies in bipolar patients of possible structural changes (magnetic resonance imaging (MRI)) functional changes (focusing on functional MRI (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT)), and those examining brain chemistry (utilizing magnetic resonance spectroscopy (MRS)). Metabolic studies reviewed were those that examined 3-methoxy-4-hydroxyphenylglycol (MHPG), cellular calcium, and protein kinase C (PKC). The results clearly suggest that BPD patients differ from controls on many of these measures. However, while there is evidence from genetic studies suggesting possible differences between BPD-II patients and BPD-I patients, the neuroimaging and metabolic studies to date do not support this, and there appear to be no consistent pathophysiological differences between these subtypes from evidence available at present.
... Major depressive disorder and bipolar disorder, in which patients experience manic episodes typically interspersed with depressive episodes, are commonly referred to as mood disorders. These are debilitating and prevalent illnesses, with a lifetime incidence of approximately 20% in the United States, and they are life-threatening due to suicide as well as other causes (Wong and Licinio, 2001; Nestler et al., 2002; Berns and Nemeroff, 2003; Belmaker, 2004). The pathophysiological underpinnings of mood disorders are unknown. ...
The mood disorders major depressive disorder and bipolar disorder are prevalent, are inadequately treated, and little is known about their etiologies. A better understanding of the causes of mood disorders would benefit from improved animal models of mood disorders, which now rely on behavioral measurements. This review considers the limitations in relating measures of rodent behaviors to mood disorders, and the evidence from behavioral assessments indicating that glycogen synthase kinase-3 (GSK3) dysregulation promotes mood disorders and is a potential target for treating mood disorders. The classical mood stabilizer lithium was identified by studying animal behaviors and later was discovered to be an inhibitor of GSK3. Several mood-relevant behavioral effects of lithium in rodents have been identified, and most have now been shown to be due to its inhibition of GSK3. An extensive variety of pharmacological and molecular approaches for manipulating GSK3 are discussed, the results of which strongly support the proposal that inhibition of GSK3 reduces both depression-like and manic-like behaviors. Studies in human postmortem brain and peripheral cells also have identified correlations between alterations in GSK3 and mood disorders. Evidence is reviewed that depression may be associated with impaired inhibitory control of GSK3, and mania by hyper-stimulation of GSK3. Taken together, these studies provide substantial support for the hypothesis that inhibition of GSK3 activity is therapeutic for mood disorders. Future research should identify the causes of dysregulated GSK3 in mood disorders and the actions of GSK3 that contribute to these diseases.
... In addition to schizophrenia and control subjects, we have included bipolar subjects in the genotyping and brain gene expression as well. Bipolar disorder (BD) illness affects approximately 0.8 – 1.6% of the population (Kessler et al. 1997) and is characterized by cyclical episodes of mania and depression, with a return to normal state between episodes (Berns and Nemeroff 2003). There is a significant genetic component to BD based upon twin studies; BD has an estimated heritability as high as 93% (Kieseppa et al. 2004). ...
A missense polymorphism in the NRG1 gene, Val>Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val>Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n=358), schizophrenia (SZ, n=273), or unrelated controls (CO, n=479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val>Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain-specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study.
... Estimates of the prevalence of bipolar I disorder have ranged from 0.8% to 1.6% of the general population (Berns and Nemeroff, 2003). The disorder is primarily defined by a history of a manic episode, although many patients experience both manic and depressive episodes. ...
Although genetic influences on bipolar I disorder are well established, localization of genes that predispose to the illness has been difficult. Some genes predisposing to bipolar I disorder may be transmitted without expression of the categorical clinical phenotype. One strategy to overcome this obstacle is the use of quantitative endophenotypes, as has been done for other medical disorders.
We analyzed 30 bipolar I extended families (300 subjects, average family size 10.34 members, range: 2-31) and 20 unrelated healthy controls from a Costa Rican sample. Heritability and genetic correlation of the state and trait scale from the Anxiety State and Trait Inventory was computed by using the general linear model (SOLAR package software). We also assessed variation of both scores among groups (patients, relatives and controls) and tested independence of affection status.
Heritability for state is 0.45 (SE=0.11, p=0.0000001) and for trait is 0.89 (SE=0.06, p=6.22e-29). Genetic correlation for state and trait is 0.29, (SE=0.12, p=0.038-3.19e-8). Bipolar I patients showed the highest trait score (F=12.17 [5,24], p=0.002), (bipolar I patients>relatives with other pathologies, >healthy relatives>unrelated healthy controls) with normal distribution in healthy individuals and no difference regarding depression and mania current status, (F=0.230, df=1, p=0.632 and F=1.401, df=1, p=0.238, respectively), contrary to the state score.
Confounding factors such as comorbid disorders could affect the interaction of subclinical anxiety with mania. Due to our limited budget we were not able to re-evaluate the subjects and conduct a test retest to assess the STAI reliability and mood state independence of anxiety traits over different times. Further research is needed to evaluate if anxiety traits are specially related to bipolar I disorder in comparison with other traits such as anger, attention or response inhibition deficit, pathological impulsivity or low self-directedness.
Anxiety state and trait are heritable and share some genetic factors but only trait showed normal distribution in healthy subjects, mood current status independence and significant liability for bipolar I disorder. A stair-step distribution of trait anxiety scores in the family members and controls based on their genetic proximity to affected individuals and diagnostic status suggests that trait anxiety could be an endophenotype in these bipolar I families.
... 74 Similarly, bipolar disorder leaves no neurobiological "smoking gun" although evidence points to a disorder of cellular signal transduction. 75 It does share some overlap with schizophrenia, including prefrontal cortical volume loss, 76 increased white matter hyperintensities, 77 and alterations to myelin-related gene expression. 78 The adolescent or early adulthood form of Niemann-Pick type C may disrupt neurodevelopmental processes occurring during this period of CNS development, such as frontotemporal myelination, 79 impairing frontotemporal connectivity that may lead to psychosis. ...
Psychotic symptoms occur in a variety of medical and neurological conditions. The authors describe three young men with a variant form of Niemann-Pick type C disease, a neurodegenerative disorder related to abnormal intracellular cholesterol metabolism, who presented with psychosis in early adulthood. Two patients were treated for schizophrenia for many years prior to a diagnosis of Niemann-Pick type C. The cases presented in this article illustrate the role of changes in both white and gray matter structures in psychosis, and, like the assessments of other neurodevelopmental disorders that predispose toward psychotic presentations, shed light on the underlying pathophysiology of major mental disorders.
The care of stroke patients has changed dramatically. As well as improvements in the emergency care of the condition, there have been marked advances in our understanding, management and rehabilitation of residual deficits. This book is about the care of stroke patients, focusing on behavioural and cognitive problems. It provides a comprehensive review of the field covering the diagnostic value of these conditions, in the acute and later phases, their requirements in terms of treatment and management and the likelihood and significance of long-term disability. This book will appeal to all clinicians involved in the care of stroke patients, as well as to neuropsychologists, other rehabilitation therapists and research scientists investigating the underlying neuroscience.
Bipolar disorder I (BD-I) and bipolar disorder II (BD-II) have specific characteristics and clear diagnostic criteria, but quite different treatment guidelines. In clinical practice, BD-II is commonly mistaken as a mild form of BD-I. This study uses data science technique to identify the important Single Nucleotide Polymorphisms (SNPs) significantly affecting the classifications of BD-I and BD-II, and develops a set of complementary diagnostic classifiers to enhance the diagnostic process. Screening assessments and SNP genotypes of 316 Han Chinese were performed with the Affymetrix Axiom Genome-Wide TWB Array Plate. The results show that the classifier constructed by 23 SNPs reached the area under curve of ROC (AUC) level of 0.939, while the classifier constructed by 42 SNPs reached the AUC level of 0.9574, which is a mere addition of 1.84%. The accuracy rate of classification increased by 3.46%. This study also uses Gene Ontology (GO) and Pathway to conduct a functional analysis and identify significant items, including calcium ion binding, GABA-A receptor activity, Rap1 signaling pathway, ECM proteoglycans, IL12-mediated signaling events, Nicotine addiction), and PI3K-Akt signaling pathway. The study can address time-consuming SNPs identification and also quantify the effect of SNP-SNP interactions.
Background: Resolvin D1 (RvD1) is a soluble mediator, which is the metabolite of docosahexaenoic acid (DHA), an omega-3 fatty acid. It is thought that RvD1 may contribute to the etiology of bipolar disorder (BD) because of its anti-inflammatory and antidepressant effect. In this study, it was aimed to compare the serum RvD1 levels of patients with BD diagnosed manic-depressive-euthymic episodes with those of healthy subjects. The secondary objective of this study is to investigate the relationship between RvD1 measures and inflammatory markers.
Methods: We included 121 male patients with BD type I, 44 in a mania, 35 in depression and 42 in euthymic state, and 41 healthy controls. Serum RvD1 levels and inflammation indicators (CRP, neutrophil, leukocyte, and albumin) were measured.
Results: When the RvD1 values of patients were compared, the median (interquartile range) RvD1 value was 11.2 (5.2) for manic patients, 11.2 (6.6) for depressive patients, 9.6 (5.6) for euthymic patients and 8.4 (7.7) for the control group. There were statistically significant differences between the groups in terms of RvD1 values (p < .001). After adjustment for age and current state with ANCOVA, there were statistically significant differences between manic vs. control groups and depression vs. control groups (p < .001, p=.047). Also mean CRP measures (p=.029) and neutrophil counts (p=.009) were significantly correlated with log transformed RvD1 levels.
Conclusions: Our results of increased anti-inflammatory RvD1 during manic and depressive states suggest RvD1 may serve as a delayed resolvent possibly improving inflammatory imbalance. Further research is needed to confirm our findings.
Glycogen synthase kinase-3 is a multi-functional serine-threonine kinase and is involved in diverse physiological processes, including metabolism, cell cycle, and gene expression by regulating a wide variety of known substrates like glycogen synthase, tau-protein and ?-catenin. Aberrant GSK-3 has been involved in diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. In this review, we present an overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation. In addition, a detailed description of the small molecule inhibitors of GSK-3 with different mode of action discovered or specifically developed for GSK-3 has been presented. Furthermore, some clues for the future optimization of these promising molecules to develop specific drugs inhibiting GSK-3, for the treatment of associated disease conditions have also been discussed.
GSK-3 specific inhibitors are promising candidates for the treatment of devastating pathologies such as diabetes, neurodegenerative diseases and cancers. We have synthesized a library of pyrimidin-4-one-1,2,3-triazole conjugates using click-chemistry approach and evaluated them as glycogen synthase kinase-3β inhibitors. Compounds 3g, 3j, 3n and 3r were found to be most potent among the eighteen pyrimidin-4-one-1,2,3-triazole conjugates synthesized and they were further evaluated for their in vivo anti-depressant activity. Compound 3n (2-((1-(3,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-methyl-6-phenylpyrimidin-4(3H)-one) exhibited the most potent inhibitory activity against GSK-3β with IC50 value of 82 nM and was also found to exhibit significant antidepressant activity at 50 mg/kg, when compared with fluoxetine, a known antidepressant drug. The molecular docking studies were performed to elucidate the binding modes of the compounds with the GSK-3β target and two crucial interactions namely, hydrogen bond formation with Val 135 and Lys 183 residues in the active site of GSK-3β were observed.
Introduction Challenges in Prescribing Psychotropic Medications Assessment Performing the Psychiatric Interview Physical Exam Formulation of a Diagnosis and Plan Need for Consultation Patient Family Education Review of Common Psychiatric Medications Drug-Drug Interactions Antipsychotics Summary References
Several brain structures play a germane role in the development and maintenance of symptoms in depression. Current studies in treatment-resistant depression (TRD) are targeting the nucleus accumbens (NAc), the medial forebrain bundle, the anterior cingulate cortex (Cg25), and the anterior limb of the internal capsule. The NAc has been studied as a target site for deep brain stimulation (DBS) in depression because of its prominent role in the reward system. The first evidence on a small sample studied for up to 4 years has proven that NAc DBS induces stable, sustained antidepressant effects in 50 % of patients. It is not yet possible to decide on the optimal target for DBS in TRD: the studies are small, long-term data are only available for up to 5 years, and the stimulation amplitude is high compared with neurological indications. The medial forebrain bundle—connecting frontal DBS targets (Cg25) with the NAc—has recently been proposed as new hypothesis-driven target awaiting clinical evidence. The application of NAc DBS for the treatment of bipolar disorder and other psychiatric diseases (e.g., alcohol dependency, opioid addiction, schizophrenia) is currently being investigated. No fundamental ethical objections to the use of DBS in psychiatric disorders have been put forward, but until substantial clinical data are available, mandatory standards are needed to prevent harming patients.
Bipolar disorder coexists with other psychiatric diagnoses and medical comorbidities. The objective of this case report and selective review of the literature is to divulge the comorbidity in bipolar disorder manic episode with psychotic features with a chronic hyperprolactinemic state. We report a female patient 30 years of age with galactorrhea of 6 years of evolution before the onset of any psychiatric treatment. During the study period had two manic episodes with psychotic features, requiring hospitalization on both occasions. Her symptoms subsided in 9 days with treatment with haloperidol and magnesium valproate. We discuss the treatment used and the indication of a second-generation antipsychotic effective in bipolar disorder profile and more appropriate to the circumstances of the case, including the finding of chronic hyperprolactinemia, which after ruled out as causes pituitary adenoma and hypothyroidism, was associated with other findings: polycystic ovaries. Finally, we analyze the probable participation of hyperprolactinemia as a trigger a manic episode.
Introduction Alteration of level of consciousness (ALC), which comprises deficient arousal, stupor, and rarely deep coma, is frequent at the acute stage of stroke. These conditions may cause fluctuating, fixed, or fast decrease of consciousness level, which in turn interferes with a detailed bedside neurological examination and neuropsychological assessment. Conversely, ALC constitutes a useful complementary sign both for the localization (syndrome) and cause (etiology) of cerebrovascular diseases (Adams, 1997). A typical example is the examination of a stuporous old patient with high blood pressure (220/120 mmHg), showing an ataxic hypesthetic hemiparesis with asterixis, bilateral Babinski signs, whereas neuro-ophthalmological evaluation of his (forced open) eyes reveals an upgaze palsy with downward gaze deviation: this stroke pattern suggests a contralateral large thalamic (syndrome) hemorrhage (etiology), as illustrated in Figure 23.1. Patients who develop ALC, ranging from somnolence to stupor and coma, need immediate admission to the intensive care unit (ICU), particularly those without upper airways protection, absent gag reflex, and/or a Coma Glasgow Scale (CGS) below or equal to 6 (see later). Indeed, endotracheal intubation is mandatory in these cases before further CT-scan or MR imaging (MRI) studies, EEG and laboratory tests – i.e. hematocrit, electrolytes with quick capillary glucose, osmolality; renal, hepatic, arterial blood gases (pH, PCO2, PO2, HCO3, HbCO, lactate), coagulations tests (aPTT, INR, platelets, smear, fibrinogen with fibrin degeneration products, d-dimer), blood and urine toxic screening, thyroid and hypophyse functions screening.
Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Bipolar disorder is a serious, recurrent disabling psychiatric illness characterised by episodes of mania and depression. The two major types of bipolar disorder (type I and type II), differ in the severity and duration of symptoms, and have a combined prevalence of approximately 1-2%, imposing an annual cost to the UK economy of about £2 billion. Other classifications of bipolar disorder include mixed episodes of mania and depression or rapid cycling between mania and depression. Bipolar disorder is a leading worldwide cause of disability and is associated with a particulary high risk of suicide. Other psychiatric disorders such as anxiety and substance abuse are also frequently comorbid with bipolar disorder. Misdiagnosis is common because of the variable presentation of the disorder. For example, if depressive episodes are the first symptoms manifested, patients are often mistakenly diagnosed with unipolar depression. Treatment of such patients with antidepressants, particularly in the absence of a mood stabiliser, can precipitate manic episodes. Moreover, in more chronic cases treatment with antidepressants alone may result in the development of the more serious and difficult-to-treat, rapid-cycling disorder. Thus, it is vitally important that physicians working in primary care recognise potential cases of bipolar disorder and use short screening questionnaires if bipolar disorder is suspected. Recent guidelines published by the National Institute for Health and Clinical Excellence (NICE) highlight the need for better recognition of bipolar disorder in the community allied with a reduction in suboptimal care in order to substantially improve the outcomes of affected patients.
A third of patients suffering from major depression cannot be helped by conventional treatment methods. These patients face reduced quality of life, high risk of suicide, and little hope of recovery. Deep brain stimulation (DBS) is under scientific evaluation as a new treatment option for these treatment-resistant patients. First clinical studies with small samples have been stimulated at the subgenual cingulate gyrus (Cg25/24), the anterior limb of the capsula interna (ALIC), and the nucleus accumbens (NAcc). Long-term antidepressant effects, augmentation of social functioning, and normalization of brain metabolism have been shown in about 50% of patients. Cognitive safety regarding attention, learning, and memory has been reported. Adverse events were wound infection, suicide, and hypomania, amongst others. Larger studies are under way to confirm these preliminary encouraging results. New hypothesis-guided targets (e.g., medial forebrain bundle, habenula) are about to be assessed in clinical trials. The application of DBS for other psychiatric diseases (e.g., bipolar disorder, alcohol dependency, opioid addiction, schizophrenia) is debated and single case studies are under way. Standards are needed for study registration, target selection, patient inclusion and monitoring, and publication of results to guarantee safety for the patients and scientific exchange.
Bipolar disorder (BD) has been consistently associated with altered levels of oxidative stress markers, although the cause and consequences of these alterations remain to be elucidated. One of the main hypotheses regarding the pathogenesis of mania involves increased dopaminergic transmission. In this review, the authors aim to discuss a potential mechanism by which increased oxidative stress inhibits the uptake of dopamine through the post-translational modification of the dopamine transporter and its implications for BD. Within the next 5 years, the authors believe that the mechanisms of dopamine transporter oxidation and its impact on the pathophysiology of BD will be elucidated, which may open avenues for the development of more specific interventions for the treatment of this debilitating illness.
Neuropsychological processes may have direct bearing on the emotional dysregulation and functional impairments characteristic of bipolar disorder. Neuropsychological deficits that have been identified in adults and children with bipolar disorder include impairments in executive functions, declarative memory, attentional processes, and possibly working memory. Structural and functional magnetic resonance imaging and magnetic resonance spectroscopy studies of adults and children with bipolar disorder also indicate abnormalities in regions thought to underlie these neuropsychological deficits, including the basal ganglia, amygdala, and dorsolateral, orbitofrontal, and anterior cingulate cortices. Study of this area is made challenging by the heterogeneity of bipolar disorder, the heterogeneity of neuropsychological deficits among groups of patients with different clinical characteristics, the lack of specificity of neurocognitive deficits for bipolar disorder, and difficulty ascertaining whether deficits are inherent in the disorder, predate the disorder, or are influenced by mood state, course, treatment, and comorbidity with other disorders. In this review, we integrate the literature on neuropsychological functioning and neuroimaging in both children and adults with bipolar disorder, propose a nascent integrative model of cognitive function in bipolar disorder, and make suggestions for future studies and model development.
This study compared the structure of cognitive ability (specifically, verbal/crystallized [Gc] and visual-spatial ability [Gv]), as measured in the Wechsler Intelligence Scale for Children, in youth with manic symptoms with a nationally representative group of similarly aged youth. Multigroup confirmatory factor analysis found the majority of the estimated parameters were invariant between the groups, although there was a difference in the intercepts for the Similarities subtest and difference in unique variances for the Picture Completion, Comprehension, and Picture Arrangement subtests. Thus, although there are many neurological changes associated with manic symptoms, the structure of verbal/crystallized and visual-spatial abilities appear relatively robust and invariant. As Gc and Gv are thspatial abilities appear relatively robust and invariant. As Gc and Gv are the primary domains on all the Wechsler Intelligence Scales for Children, results also indicate that clinical interpretation of the Wechsler scales may be appropriate to measure cognitive performance in youths with manic symptoms.
Postmortem, genetic, brain imaging, and peripheral cell studies all support decreased mitochondrial activity as a factor in the manifestation of Bipolar Disorder (BD). Because abnormal mitochondrial morphology is often linked to altered energy metabolism, we investigated whether changes in mitochondrial structure were present in brain and peripheral cells of patients with BD. Mitochondria from patients with BD exhibited size and distributional abnormalities compared with psychiatrically-healthy age-matched controls. Specifically, in brain, individual mitochondria profiles had significantly smaller areas, on average, in BD samples (P = 0.03). In peripheral cells, mitochondria in BD samples were concentrated proportionately more within the perinuclear region than in distal processes (P = 0.0008). These mitochondrial changes did not appear to be correlated with exposure to lithium. Also, these abnormalities in brain and peripheral cells were independent of substantial changes in the actin or tubulin cytoskeleton with which mitochondria interact. The observed changes in mitochondrial size and distribution may be linked to energy deficits and, therefore, may have consequences for cell plasticity, resilience, and survival in patients with BD, especially in brain, which has a high-energy requirement. The findings may have implications for diagnosis, if they are specific to BD, and for treatment, if they provide clues as to the underlying pathophysiology of BD.
Written for the Dept. of Human Genetics. Thesis (M.Sc.). Includes bibliographical references.
Prepulse inhibition (PPI) is a measure of sensorimotor gating or information processing. Few studies have examined PPI in bipolar disorder (BD); two studies reported a PPI disruption and two reported no change. There are gender differences in PPI and within the clinical profile of BD, which may explain some of these discrepancies. Thus, the effect of gender on PPI in BD was the focus of the current study. Euthymic BD patients (14 male/15 female) were compared to age- and IQ-matched healthy control participants (16 male/16 female). Assessment of PPI included 21 pulse-alone trials (115 dB) and a total of 42 prepulse-pulse trials (seven of each prepulse: 74, 78, 86 dB) at two stimulus onset asynchrony levels (SOA: 60, 120 ms). There was a group x SOA and a group x gender interaction, reflecting that men with BD showed reduced PPI compared to control males at the 60-ms SOA (3% in BD vs. 26% in controls), but not the 120-ms SOA. In contrast, women with BD had significantly increased PPI compared to female controls at the 120-ms SOA (49% in BD vs. 29% in controls), but not the 60-ms SOA. Compared to control participants BD patients showed changes in PPI, which are gender-dependent; male BD participants had reduced PPI, whereas female BD participants had increased PPI. This gender difference highlights the need to consider men and women with BD as two distinct groups, at least in PPI studies.
Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n=10) and healthy controls (n=10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (V(max)) and affinity constant (K(m)) were determined. A significantly lower V(max) for tyrosine (p=0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in K(m) for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low V(max)) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.
Premorbid adjustment (PMA) in schizophrenia (SZ) has been widely studied and shown to be worse in individuals who develop SZ as compared to controls. It has been proposed as a predictor of clinical presentation and outcome, and may delineate a specific SZ phenotype for genetic and other biological studies. Research into PMA in BD has been scarce and inconclusive.
The authors compared PMA in individuals suffering from BD with that of healthy controls and investigated whether levels of PMA in BD patients correlate with specific phenotypic features.
The authors investigated 344 BD patients and 137 population-based controls. Retrospective PMA assessment was performed using the Premorbid Adjustment Scale (PAS). An overall score as well as sub-scores for age ranges and functional domains were obtained.
Patients had a better overall PAS score than controls and outperformed controls during early and late adolescence. They scored significantly better than controls in the functional domains "sociability and withdrawal" and "adaptation to school". No differences were observed for the other subscales and there were no differences between groups during childhood. No association was observed between PMA and any of the phenotype characteristics investigated.
In the largest study to date on PMA in BD, PMA was shown to be better in bipolar patients than in healthy controls. PMA in BD is not a simple proxy for commonly studied phenotypic markers of severity. PMA emerges as a phenotype in its own right, and highlights an aspect of disparity rather than overlap between SZ and BD.
The pathophysiology of abnormal mood states-mania and depression-in patients with bipolar disorder remains unclear. Facial affect processing paradigms are an effective way of studying behavioral and functional magnetic resonance imaging (fMRI) correlates of affective disorders.
We used a factorial design to measure the neural correlates of tasks, tapping explicit and implicit recognition of sad, fearful, and happy facial expressions using event-related fMRI paradigms in three groups of participants: eight bipolar depressed patients, eight bipolar manic patients, and eight control subjects.
Depressed and manic patients exhibited overactivated responses to fearful faces, as well as to mood-incongruent facial expressions, with the depressed group exhibiting overactivity in fronto-striato-thalamic systems in response to happy faces and the manic group exhibiting overactivity in the fusiform gyrus in response to sad faces. For manic patients, task type also affected the neural response to sad faces, with the corticolimbic regions showing overactivation for implicit processing and underactivation for explicit processing.
Depressed and manic patients exhibited abnormal neural responses to sad, fearful, and happy facial expressions. Additionally, the attentional level of sad facial affect processing has important consequences for abnormalities of amygdala and cingulate activation in manic patients.
Neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation. Magnetic resonance imaging (MRI) techniques sensitive to changes in cerebral blood flow and blood oxygenation were developed by high-speed echo planar imaging. These techniques were used to obtain completely noninvasive tomographic maps of human brain activity, by using visual and motor stimulus paradigms. Changes in blood oxygenation were detected by using a gradient echo (GE) imaging sequence sensitive to the paramagnetic state of deoxygenated hemoglobin. Blood flow changes were evaluated by a spin-echo inversion recovery (IR), tissue relaxation parameter T1-sensitive pulse sequence. A series of images were acquired continuously with the same imaging pulse sequence (either GE or IR) during task activation. Cine display of subtraction images (activated minus baseline) directly demonstrates activity-induced changes in brain MR signal observed at a temporal resolution of seconds. During 8-Hz patterned-flash photic stimulation, a significant increase in signal intensity (paired t test; P less than 0.001) of 1.8% +/- 0.8% (GE) and 1.8% +/- 0.9% (IR) was observed in the primary visual cortex (V1) of seven normal volunteers. The mean rise-time constant of the signal change was 4.4 +/- 2.2 s for the GE images and 8.9 +/- 2.8 s for the IR images. The stimulation frequency dependence of visual activation agrees with previous positron emission tomography observations, with the largest MR signal response occurring at 8 Hz. Similar signal changes were observed within the human primary motor cortex (M1) during a hand squeezing task and in animal models of increased blood flow by hypercapnia. By using intrinsic blood-tissue contrast, functional MRI opens a spatial-temporal window onto individual brain physiology.
This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States.
The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview.
Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status.
The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.
Using magnetic resonance imaging (MRI), we studied brain morphometric differences between patients with first-episode mania (n = 17) and normal control subjects (n = 16). Patients were admitted for their first psychiatric hospitalization and met DSM-III-R criteria for bipolar disorder, manic or mixed. Diagnoses were made using the Structured Clinical Interview for DSM-III-R. Patients and control subjects were matched for age, gender, height, past history of substance abuse, and handedness, although control subjects had attained higher levels of education. MRI inversion recovery coronal scans were used for measurements. Volumetric measurements were obtained for cerebral hemispheres, lateral and third ventricles, caudate, thalamus, and cingulate gyrus. Patients with first-episode mania demonstrated significantly larger third-ventricular volumes, possibly increased lateral ventricular volumes, and differences in gray/white matter distribution compared with normal control subjects. The possible pathophysiological meaning of these findings is discussed.
Objective: Accumulating evidence suggests a greater number of T-2 abnormalities in the brains of patients with bipolar I disorder. The authors sought to evaluate the presence of signal ''hyperintensities'' in both bipolar I and II subjects and systematically review the existing literature. Method: Magnetic resonance images of the brain were obtained prospectively for 29 patients with bipolar I disorder, 26 patients with bipolar II disorder, and 20 normal comparison subjects. The presence and location of signal hyperintensities in three brain regions (periventricular white matter, subcortical gray matter, and deep white matter) were evaluated. Results: No significant differences were found between groups for the presence of subcortical gray or deep white matter hyperintensities. Periventricular hyperintensities were more common in bipolar I patients (62%) than in bipolar II patients (38%) and normal comparison subjects (30%). Within patient groups, medication use was not significantly different for those with or without the presence of white matter hyperintensities. The literature on bipolar disorder and signal hyperintensities is reviewed. A meta-analysis of the pooled data in the literature on bipolar illness and signal hyperintensities revealed that the odds of having a T-2 hyperintensity are significantly greater for bipolar I than for normal comparison subjects. Conclusions: Having bipolar I disorder significantly increases the chance of having white matter changes in the brain. This study suggests that bipolar II patients may be more similar than bipolar I patients to comparison subjects on T-2 measures. The possible pathophysiological significance of hyperintensities is discussed.
An unresolved question in neuroscience and psychology is how the brain monitors performance to regulate behavior. It has been proposed that the anterior cingulate cortex (ACC), on the medial surface of the frontal lobe, contributes to performance monitoring by detecting errors. In this study, event-related functional magnetic resonance imaging was used to examine ACC function. Results confirm that this region shows activity during erroneous responses. However, activity was also observed in the same region during correct responses under conditions of increased response competition. This suggests that the ACC detects conditions under which errors are likely to occur rather than errors themselves.
ABSTRACT— Since the clinical significance of CT abnormalities found in bipolar patients remains obscure, we studied 26 DSM-III bipolar patients who had specific CT abnormalities (third ventricle enlargement, and hyperdensity of the caudate, thalamus, anterior frontal white matter, and right temporal lobe) on numerous parameters such as EEG, the Halstead-Reitan Neuropsychological Battery, premorbid personality adjustment, family history of affective disorder, positive and negative symptoms, employment history, and response to lithium carbonate treatment. None of these measures could differentiate between the CT abnormal and CT normal subgroups. The implications of these findings are discussed.
• Several studies, conducted in psychiatric settings, have reported that the dexamethasone suppression test (ST) is useful in the diagnosis of endogenous depression. To determine whether the test has clinical utility in internal medicine practice, data were reviewed and reanalyzed from all studies that evaluated the dexamethasone ST in the diagnosis of depression. In these 11 studies, the mean positive predictive value reported for the test was 84%, reflecting high prevalence of disease (50%), sensitivity (43%), and specificity (92%) in those specialized populations studied. When estimates of the prevalence and severity of conditions associated with depressed mood seen in internal medicine were used, the sensitivity dropped to 30%, and the specificity to 85%. Assuming a prevalence of 20%, a figure based on available epidemiologic data, the predictive value for a positive test would be 33%, too low to have value in most clinical settings. Data from studies currently available do not support the use of dexamethasone ST in internal medicine practice. More generally, before any test is adopted in a general medical setting, it should be studied in that setting, or available data should be reanalyzed to correct for biases affecting prevalence, sensitivity, and specificity that may inflate the test's value.
(Arch Intern Med 1983;143:2085-2088)
• As part of a study of the effects of lithium carbonate on neurochemical function in man, platelet and lymphocyte adenylate cyclase activity and lymphocyte β-adrenergic receptor binding characteristics were determined before and after 2 weeks of lithium treatment in 10 normal volunteers. Lithium had differential effects on platelet and lymphocyte adenylate cyclase activity. In platelets, basal and stimulated (guanyl imidodiphosphate [Gpp[NH]p] or cesium fluoride) adenylate cyclase activity was significantly augmented by lithium treatment. By contrast, in lymphocytes, Gpp(NH)p- and cesium fluoride—stimulated adenylate cyclase activity was unaffected, while basal activity was decreased modestly after lithium. These results are consistent with preclinical studies that suggest that lithium's effects on adenylate cyclase activity are specific with respect to tissue and brain region and that lithium may interfere with guanine nucleotide binding (G) protein function. Lithium treatment significantly increased the ratio of low- to high-affinity dissociation constants for agonist displacement of antagonist binding to lymphocyte β-adrenergic receptors (thought to reflect coupling between the β-adrenergic receptor and stimulatory G protein). Lithium had significant effects on measures associated with signal transduction that might be contrasted to its more subtle effects on neuronal function (norepinephrine release) and neuroendocrine systems (responses to serotoninergic challenge) in these same subjects (reported in a companion article). Lithium's primary site of action may be on signal transduction mechanisms. These effects subsequently may be manifested in changes in neurotransmitter function that may be important to lithium's mood-stabilizing actions.
• Structural brain abnormalities were examined in a sample of 48 patients with bipolar affective disorder who were compared with 54 schizophrenic patients and 47 normal controls. As in our previous work using computed tomographic scanning, lateral ventricular enlargement was due to a diagnostic effect. In this study, the effect was more prominent in the schizophrenic men, while a trend was seen in the bipolar men. Women in both groups did not differ significantly from normal subjects. This finding is possibly consistent with the fact that men have a higher frequency of birth anomalies such as hydrocephalus. Since one cause of such birth anomalies might be periventricular hemorrhage or infarction, we also evaluated all scans for the presence of small focal regions of signal hyperintensity. A significant increase in the number of focal signal hyperintensities was noted in the bipolar patients, in comparison with normal subjects, but not in the schizophrenics. The bipolar patients with focal signal hyperintensities had a trend toward larger ventricular size than those without. The pathophysiological significance of these findings is unclear.
• Cerebral metabolic rates for glucose were examined in patients with unipolar depression (N=11), bipolar depression (N=5), mania (N=5), bipolar mixed states (N =3), and in normal controls (N = 9) using positron emission tomography and fluorodeoxyglucose F 18. All subjects were studied supine under ambient room conditions with eyes open. Bipolar depressed and mixed patients had supratentorial whole brain glucose metabolic rates that were significantly lower than those of the other comparison groups. The whole brain metabolic rates for patients with bipolar depression increased going from depression or a mixed state to a euthymic or manic state. Patients with unipolar depression showed a significantly lower ratio of the metabolic rate of the caudate nucleus, divided by that of the hemisphere as a whole, when compared with normal controls and patients with bipolar depression.
Background:
Recent reports in the literature document an association between focal white matter abnormalities in bipolar as well as unipolar mood disorder. The importance of this finding and other associated anatomic differences is uncertain.
Methods:
We examined the volume of abnormal white matter and other brain volumes using quantitative magnetic resonance imaging analysis. We explored the relationship of these variables with diagnosis, cognitive function, and clinical variables in 36 patients with bipolar disorder, 30 patients with unipolar disorder, and 26 control subjects who were free from significant medical and neurologic illness.
Results:
Younger patients with bipolar disorder (but not similarly aged patients with unipolar disorder or controls) have an increased volume of abnormal white matter. Data also indicate that the total volume of abnormal white matter may be associated with increased cognitive impairment, increased rate of psychiatric illness in the family, and onset after adolescence.
Conclusion:
Patients with bipolar disorder demonstrate a pattern of subcortical brain morphologic abnormalities and cognitive impairment.
The authors reviewed neuroimaging studies of bipolar disorder in order to evaluate how this literature contributes to the current understanding of the neurophysiology of the illness.
Papers were reviewed as identified, using the NIMH PubMed literature search systems that reported results of neuroimaging studies involving a minimum of five bipolar disorder patients compared with healthy comparison subjects.
Structural neuroimaging studies report mixed results for lateral and third ventriculomegaly. Recent studies suggest subcortical structural abnormalities in the striatum and amygdala, as well as the prefrontal cortex. Proton spectroscopic studies suggest that abnormalities in choline metabolism exist in bipolar disorder, particularly in the basal ganglia. Additionally, phosphorous MRS suggests that there may be abnormalities in frontal phospholipid metabolism in bipolar disorder. Functional studies have identified affective state-related changes in cerebral glucose metabolism and blood flow, particularly in the prefrontal cortex during depression, but no clear abnormalities specific to bipolar disorder have been consistently observed.
The current literature examining the neurophysiology of bipolar disorder using neuroimaging is limited. Nonetheless, abnormalities in specific frontal-subcortical brain circuits seem likely. Additional targeted studies are needed to capitalize on this burgeoning technology to advance our understanding of the neurophysiology of bipolar disorder.
Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors.
Sixty patients with affective illness were examined by computed tomography (CT) and compared to 60 age- and sex-matched controls. Using three different methods of measurement, no differences in ventricular brain ratio (VBR) between patients and controls could be detected. However, linear ventricular values of the frontal horns plus the bicaudate distance (Huckmann number) and the third ventricle were enlarged in the total group of patients. This was also found in subgroups of older, male, psychotic, unipolar, Dexamethasone Suppression Test (DST) positive, and lithium-treated patients when compared to individually matched controls. Younger, nonpsychotic, female, bipolar, DST-normal and non-lithium-treated patients did not differ from controls. The Huckmann number correlated with the duration of illness, as measured by the first episode and the number of episodes. The comparison between the subgroups of patients yielded higher linear and VBR values in older subjects, in men, and in psychotic subjects, whereas no differences were found in comparisons between unipolar versus bipolar, DST-positive versus DST-negative, and lithium-treated versus non-lithium-treated patients.
Thesis (M.D.)--University of Newcastle upon Tyne, 2005.
Volumetric measurements of subcortical and temporal structures were done on a sample of 54 schizophrenic patients, who were compared with 48 bipolar patients and 47 normal controls. We observed the male schizophrenic patients to have significant enlargement in the putamen and lesser enlargement in the caudate. We found the right temporal lobe to be larger than the left across all diagnostic groups, although bipolar females failed to have this asymmetry. We did not replicate the finding of decreased hippocampal, amygdala, or temporal lobe volume in our schizophrenic patients. Nor did we find significant differences between our bipolar patients and controls in the structures measured, with the exception of the right hippocampus. Our findings are consistent with a developmental defect in pruning of subcortical brain regions or with a compensatory synaptic increase secondary to decreased input from other brain regions such as the prefrontal cortex or anterior temporal lobe structures. Coupled with the lack of temporal lobe asymmetry in bipolar females, these findings suggest that different types of gender-specific neurodevelopmental abnormalities may occur in affective versus schizophrenic psychosis, which may reflect the effects of hormonal influences on brain development in predisposed individuals.
There is little information about hypothalamic-pituitary-adrenocortical (HPA) axis function in mania, particularly in mixed states. We therefore investigated HPA function and its relationship to clinical state in 19 hospitalized manic patients meeting Schedule for Affective Disorders and Schizophrenia - Research Diagnostic Criteria for acute manic episodes, compared patients with and without a mixed presentation, and examined correlations between HPA activity and behavior. Data were available from 13-16 patients. Behavioral and biochemical analyses were conducted during a 15-d placebo period. Patients with mania had elevated cerebrospinal fluid (CSF) and urinary free cortisol excretion compared with healthy subjects, and did not differ from depressed patients in any cortisol measures. Mixed manics had significantly higher morning plasma cortisol, postdexamethasone plasma cortisol and CSF cortisol than pure manics. Five of 7 mixed manics and 3 of 9 pure manics were dexamethasone suppression test (DST) nonsuppressors. Afternoon plasma cortisol and CSF cortisol correlated significantly with depressed mood; urinary free cortisol correlated with anxiety. None of the cortisol measures correlated with mania or agitation scores. These data suggest that increased cortisol secretion is a characteristic of the depressed state in mixed manics, although pure manics may also have increased DST nonsuppression.
As part of a study of the effects of lithium carbonate on neurochemical function in man, platelet and lymphocyte adenylate cyclase activity and lymphocyte beta-adrenergic receptor binding characteristics were determined before and after 2 weeks of lithium treatment in 10 normal volunteers. Lithium had differential effects on platelet and lymphocyte adenylate cyclase activity. In platelets, basal and stimulated (guanyl imidodiphosphate [Gpp[NH]p] or cesium fluoride) adenylate cyclase activity was significantly augmented by lithium treatment. By contrast, in lymphocytes, Gpp(NH)p- and cesium fluoride-stimulated adenylate cyclase activity was unaffected, while basal activity was decreased modestly after lithium. These results are consistent with preclinical studies that suggest that lithium's effects on adenylate cyclase activity are specific with respect to tissue and brain region and that lithium may interfere with guanine nucleotide binding (G) protein function. Lithium treatment significantly increased the ratio of low- to high-affinity dissociation constants for agonist displacement of antagonist binding to lymphocyte beta-adrenergic receptors (thought to reflect coupling between the beta-adrenergic receptor and stimulatory G protein). Lithium had significant effects on measures associated with signal transduction that might be contrasted to its more subtle effects on neuronal function (norepinephrine release) and neuroendocrine systems (responses to serotoninergic challenge) in these same subjects (reported in a companion article). Lithium's primary site of action may be on signal transduction mechanisms. These effects subsequently may be manifested in changes in neurotransmitter function that may be important to lithium's mood-stabilizing actions.
We examined the relative abundance of G-protein subunits in postmortem brain obtained from 7 patients with bipolar affective disorder (BAD) compared with 7 age- and sex-matched controls. G-protein subunit immunoreactivities were determined in membranes prepared from postmortem prefrontal cortex using SDS-PAGE and immunoblotting with specific polyclonal antisera against selected G-protein subunits: Gsa, Gi(1&2) alpha, Go alpha and G beta(1&2). Of these G-protein subunits, only Gs alpha immunoreactivity was found to be significantly elevated in frontal (+ 34%), and occipital (+ 80%) cortex (P less than 0.05) in BAD compared with control subjects. Smaller increments (+ 22%) in cerebellar Gs alpha immunoreactivity were also found but were not statistically significant. On the basis that increased Gs alpha immunoreactivity may reflect enhanced functional responsiveness of the receptor-effector units to which this coupling protein is integral, the present findings suggest that disturbances in Gs-mediated signal transduction may be involved in the pathophysiology of BAD.
Although mania is a rare complication of brain lesions, recent reports have emphasized the importance of lesion location and genetic predisposition in these patients. In the present study we compared patients who developed a bipolar affective disorder (i.e., mania and depression) after a brain lesion with patients who only developed mania. Although no significant between-group differences were found on demographic variables, the manic-depressed group showed significantly more impairments on the Mini Mental State Exam than the mania only group. All the bipolar patients had subcortical lesions (mainly right head of the caudate and right thalamus), while patients with unipolar mania had significantly higher frequency of cortical involvement (mainly right orbitofrontal and basotemporal cortices). It is suggested that subcortical and cortical right hemisphere lesions may produce different neurochemical and/or remote metabolic brain changes that may underlie the production of either a bipolar disease or a unipolar mania.
Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high fields, we demonstrate in vivo images of brain microvasculature with image contrast reflecting the blood oxygen level. This blood oxygenation level-dependent (BOLD) contrast follows blood oxygen changes induced by anesthetics, by insulin-induced hypoglycemia, and by inhaled gas mixtures that alter metabolic demand or blood flow. The results suggest that BOLD contrast can be used to provide in vivo real-time maps of blood oxygenation in the brain under normal physiological conditions. BOLD contrast adds an additional feature to magnetic resonance imaging and complements other techniques that are attempting to provide positron emission tomography-like measurements related to regional neural activity.
Structural brain abnormalities were examined in a sample of 48 patients with bipolar affective disorder who were compared with 54 schizophrenic patients and 47 normal controls. As in our previous work using computed tomographic scanning, lateral ventricular enlargement was due to a diagnostic effect. In this study, the effect was more prominent in the schizophrenic men, while a trend was seen in the bipolar men. Women in both groups did not differ significantly from normal subjects. This finding is possibly consistent with the fact that men have a higher frequency of birth anomalies such as hydrocephalus. Since one cause of such birth anomalies might be periventricular hemorrhage or infarction, we also evaluated all scans for the presence of small focal regions of signal hyperintensity. A significant increase in the number of focal signal hyperintensities was noted in the bipolar patients, in comparison with normal subjects, but not in the schizophrenics. The bipolar patients with focal signal hyperintensities had a trend toward larger ventricular size than those without. The pathophysiological significance of these findings is unclear.
Experiments show that sleep loss can trigger symptoms of mania or hypomania in certain bipolar patients. Exposure to light might have a similar effect in some patients with seasonal forms of bipolar illness. Attention to the possible role of sleep loss and light as triggering factors in the pathogenesis of mania may help clinicians and patients to identify some of the factors that influence the natural course of the bipolar illness and to devise strategies for its prevention and treatment.
Twenty affective disorder patients (16 bipolar and 4 unipolar) and 24 normal controls received scans with positron emission tomography (PET) using [18F]2-deoxyglucose (FDG) as a tracer. Subjects received a series of brief electrical stimuli to their right arms during FDG uptake. Patients with bipolar affective illness had significantly lower frontal to occipital glucose metabolic rate ratios (relative hypofrontality) and significantly lower metabolic rates in their basal ganglia in comparison to whole slice metabolism than normal controls. Patients with unipolar illness showed significantly higher frontal to occipital ratios, and also showed relatively decreased metabolism in the basal ganglia. All results in unipolar patients should be considered exploratory due to the small number of patients. Clinical depression ratings correlated negatively with whole slice metabolic rate.
Based on clinical similarities with schizophrenics and previous computed tomography (CT) studies that found distinct structural abnormalities in the brains of bipolar patients, we evaluated 26 DSM-III bipolar patients and 22 controls by CT, using quantitative measures of ventricular and sulcal size and of cerebral parenchymal density. Third ventricle size was increased, as was periventricular and cortical density. Comparison is made with results found in other psychotic conditions and the possible etiopathological significance discussed.
Cerebral metabolic rates for glucose were examined in patients with unipolar depression (N = 11), bipolar depression (N = 5), mania (N = 5), bipolar mixed states (N = 3), and in normal controls (N = 9) using positron emission tomography and fluorodeoxyglucose F 18. All subjects were studied supine under ambient room conditions with eyes open. Bipolar depressed and mixed patients had supratentorial whole brain glucose metabolic rates that were significantly lower than those of the other comparison groups. The whole brain metabolic rates for patients with bipolar depression increased going from depression or a mixed state to a euthymic or manic state. Patients with unipolar depression showed a significantly lower ratio of the metabolic rate of the caudate nucleus, divided by that of the hemisphere as a whole, when compared with normal controls and patients with bipolar depression.
The "catecholamine hypothesis of affective disorders" proposes that some, if not all, depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines. Evidence supporting this hypothesis was reviewed.
Data from pharmacological studies, mainly in animals, suggest that the actions of both major classes of antidepressant drugs are mediated through the catecholamines. The monoamine oxidase inhibitors increase brain concentrations of norepinephrine while imipramine-like agents potentiate the physiological effects of norepinephrine. Reserpine, a drug which can cause clinical depression, depletes catecholamines, but other amines may also be involved in its mechanism of action. A rigorous extrapolation from pharmacological studies to pathophysiology clearly cannot be made. Clinical studies relevant to the catecholamime hypothesis are limited and the findings are inconclusive.
It is not possible, therefore, to confirm definitively or to reject the catecholamine hypothesis on the basis of data currently available. In our present state of knowledge, however, the catecholamine hypothesis is of considerable heuristic value, providing the investigator and the clinician with a frame of reference integrating much of our experience with those pharmacological agents which produce alterations in human affective states.
The authors describe two patients with secondary mania associated with right thalamic infarctions. Both patients exhibited hemisensory loss, denial of illness, and amnesia for the manic episode. One improved with lithium therapy and the other recovered without specific pharmacologic intervention. A review of reported cases reveals that most focal lesions associated with secondary mania involve the diencephalic region and that the majority of lateralized lesions are on the right side.
Several studies, conducted in psychiatric settings, have reported that the dexamethasone suppression test (ST) is useful in the diagnosis of endogenous depression. To determine whether the test has clinical utility in internal medicine practice, data were reviewed and reanalyzed from all studies that evaluated the dexamethasone ST in the diagnosis of depression. In these 11 studies, the mean positive predictive value reported for the test was 84%, reflecting high prevalence of disease (50%), sensitivity (43%), and specificity (92%) in those specialized populations studied. When estimates of the prevalence and severity of conditions associated with depressed mood seen in internal medicine were used, the sensitivity dropped to 30%, and the specificity to 85%. Assuming a prevalence of 20%, a figure based on available epidemiologic data, the predictive value for a positive test would be 33%, too low to have value in most clinical settings. Data from studies currently available do not support the use of dexamethasone ST in internal medicine practice. More generally, before any test is adopted in a general medical setting, it should be studied in that setting, or available data should be reanalyzed to correct for biases affecting prevalence, sensitivity, and specificity that may inflate the test's value.
In a two-year period, 186 patients were admitted from Heathrow Airport to the nearest psychiatric hospital. Affective illness was related to time zone change. Depression was diagnosed significantly more often on flights from east to west (P less than 0.012 east to west versus west to east; P less than 0.015 north to south combined with south to north versus east to west, Fisher's exact probability test, two tailed). Hypomania was inversely related to depression in an east to west comparison (P less than 0.025). No other associations with direction of travel were seen in other diagnoses. Ninety-three (50 per cent) were diagnosed as schizophrenic; 24 of these had been aimlessly wandering. Twenty patients had been admitted at least once before under similar circumstances. Schizophrenic patients from Heathrow constituted 20 per cent of the total number of schizophrenic patients admitted to the hospital during that period.
Levels of norepinephrine (NE), serotonin (5-HT), dopamine (DA), and their major metabolites were determined in postmortem brain obtained from nine subjects with antemortem histories meeting DSM-III-R criteria for bipolar affective disorder. Compared with controls, no statistically significant differences were found in mean levels of NE, 5-HT, or DA in any brain area of bipolar subjects. NE turnover as estimated by the ratio of the major NE metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) to NE was increased in frontal (+107%), temporal (+103%), and occipital (+64%) cortex and thalamus (+83%). Significant decreases were found in the major 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), in frontal (-54%) and parietal cortex (-64%), and in 5-HIAA/5-HT ratio in temporal cortex (-55%), with a trend for decreases in both measures in caudate nucleus. In addition, levels of the major DA metabolite, homovanillic acid (HVA) were significantly decreased (-46%) in parietal cortex and HVA/DA ratios were significantly reduced (-66%) in occipital cortex obtained from bipolar compared to control subjects. Our data, taken together with previous findings regarding monoamines in postmortem brain of depressed and suicide subjects, suggest that decreased 5-HT metabolite levels and turnover may be common to all mood disorders. Increased cortical NE turnover, however, may be a more important component in the pathophysiology of bipolar disorder.
Lithium remains the most widely used treatment for bipolar disorder, and this monovalent cation represents one of psychiatry's most important treatments. Despite its demonstrated efficacy in reducing both the frequency and severity of recurrent affective episodes and decades of clinical use, the molecular mechanisms underlying its therapeutic actions have not fully been elucidated. In this report, we review the exciting recent progress in the identification of key components of signal transduction pathways (in particular, guanine nucleotide-binding proteins [G proteins], adenylyl cyclases, and protein kinase C isozymes) as targets for lithium's actions and attempt to integrate these effects with the large body of data emphasizing alterations in various neurotransmitter (particularly monoaminergic) systems. Regulation of signal transduction within critical regions of the brain by lithium affects the function of multiple neurotransmitter systems and may thus explain lithium's efficacy in protecting susceptible individuals from spontaneous, stress-induced, and drug-induced cyclic affective episodes. Recent evidence has also demonstrated significant effects of lithium on the regulation of gene expression in the central nervous system, effects that may play a major role in the long-term stabilization of mood. The identification of these intracellular targets for lithium's actions offers the potential for the development of novel, improved therapeutic agents and, in conjunction with molecular genetic approaches, may facilitate our understanding of the biological factors predisposing individuals to manic-depressive illness.
Accumulating evidence suggests a greater number of T2 abnormalities in the brains of patients with bipolar I disorder. The authors sought to evaluate the presence of signal "hyperintensities" in both bipolar I and II subjects and systematically review the existing literature.
Magnetic resonance images of the brain were obtained prospectively for 29 patients with bipolar I disorder, 26 patients with bipolar II disorder, and 20 normal comparison subjects. The presence and location of signal hyperintensities in three brain regions (periventricular white matter, subcortical gray matter, and deep white matter) were evaluated.
No significant differences were found between groups for the presence of subcortical gray or deep white matter hyperintensities. Periventricular hyperintensities were more common in bipolar I patients (62%) than in bipolar II patients (38%) and normal comparison subjects (30%). Within patient groups, medication use was not significantly different for those with or without the presence of white matter hyperintensities. The literature on bipolar disorder and signal hyperintensities is reviewed. A meta-analysis of the pooled data in the literature on bipolar illness and signal hyperintensities revealed that the odds of having a T2 hyperintensity are significantly greater for bipolar I than for normal comparison subjects.
Having bipolar I disorder significantly increases the chance of having white matter changes in the brain. This study suggests that bipolar II patients may be more similar than bipolar I patients to comparison subjects on T2 measures. The possible pathophysiological significance of hyperintensities is discussed.
To investigate the phenomenon of acute psychiatric decompensation in travelers, charts of all psychiatric-emergency patients with a history of recent travel involving time-zone changes were reviewed at a major medical center in Honolulu, HI. Charts of a control group with no history of travel were also reviewed. Significantly more travelers than controls showed symptoms of depression and mania (P < .012). East-bound travelers were significantly more likely to show symptoms of mania than controls (P < .001). In an eastbound-versus-westbound comparison, significantly more eastbound travelers showed symptoms of mania, whereas significantly more westbound travelers showed symptoms of depression (P < .05). These findings support the phase-advance hypothesis of depression. Psychosocial and biologic factors that may contribute to psychiatric decompensation in travelers are discussed.
Recent reports in the literature document an association between focal white matter abnormalities in bipolar as well as unipolar mood disorder. The importance of this finding and other associated anatomic differences is uncertain.
We examined the volume of abnormal white matter and other brain volumes using quantitative magnetic resonance imaging analysis. We explored the relationship of these variables with diagnosis, cognitive function, and clinical variables in 36 patients with bipolar disorder, 30 patients with unipolar disorder, and 26 control subjects who were free from significant medical and neurologic illness.
Younger patients with bipolar disorder (but not similarly aged patients with unipolar disorder or controls) have an increased volume of abnormal white matter. Data also indicate that the total volume of abnormal white matter may be associated with increased cognitive impairment, increased rate of psychiatric illness in the family, and onset after adolescence.
Patients with bipolar disorder demonstrate a pattern of subcortical brain morphologic abnormalities and cognitive impairment.
Accumulating evidence suggests an association between abnormalities of the basal ganglia and affective disorders. The authors hypothesized that patients with bipolar disorder would demonstrate smaller basal ganglia volumes and a greater number of hyperintensities on magnetic resonance imaging than comparison subjects who were matched on age, race, sex, and education.
Volumes of the caudate, putamen, and globus pallidus were measured in 30 patients with bipolar disorder and 30 matched normal comparison subjects. The presence, number, and location of hyperintensities were also assessed.
Male patients with bipolar disorder demonstrated larger caudate volumes than male comparison subjects. Older, but not younger, patients with bipolar disorder demonstrated more hyperintensities than comparison subjects, primarily in frontal lobe white matter.
These results are not consistent with those of previous studies showing reduced basal ganglia volume in subjects with affective disorders, but they are consistent with previous findings of increased white matter hyperintensities, especially in older patients with bipolar disorder. Considered together with results from other studies, the findings suggest that the nature of basal ganglia/subcortical white matter involvement may differ according to the type of depression (unipolar versus bipolar) and the age and sex of the patient.
Findings from computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) studies of patients with depression suggest that this mood disorder is associated with regional brain dysfunction. The various elements of depression--dysphoria, anhedonia, helplessness, and sad affect--are all closely associated with changes in cerebral blood flow and/or metabolism in the frontal-temporal cortex and caudate nucleus. A compelling convergence of information from psychiatric and neurologic investigations indicates that depression is mediated by a restricted set of brain structures.
Experimental animal and peripheral blood cell studies point to guanine nucleotide regulatory (G) protein disturbances in bipolar affective disorder. We have previously reported elevated prefrontal cortex Gs alpha protein in bipolar affective disorder and have now extended these preliminary observations in a larger number of subjects, assessing the brain regional specificity of these changes in greater detail, determining the functional biochemical correlates of such changes, and evaluating their diagnostic specificity. Membrane G protein (Gs alpha, Gi alpha, Go alpha, and G beta) immunoreactivities were estimated by western blotting in postmortem brain regions obtained from 10 patients with a DSMIII-R diagnosis of bipolar affective disorder and 10 nonpsychiatric controls matched on the basis of age, postmortem delay, and brain pH. To examine whether there were functional correlates to the observed elevated Gs alpha levels, basal and GTP gamma S- and forskolin-stimulated cyclic AMP production was determined in the same brain regions. Compared with controls, Gs alpha (52-kDa species) immunoreactivity was significantly (p < 0.05) elevated in prefrontal (+36%), temporal (+65%), and occipital (+96%) cortex but not in hippocampus (+28%), thalamus (-23%), or cerebellum (+21%). In contrast, no significant differences were found in the other G protein subunits (Gi alpha, Go alpha, G beta) measured in these regions. Forskolin-stimulated cyclic AMP production was significantly increased in temporal (+31%) and occipital (+96%) cortex but not in other regions. No significant differences were apparent in basal or GTP gamma S-stimulated cyclic AMP production.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypothalamic-pituitary-adrenal system (HPA)-function in patients with mania (n = 11), depression (n = 11, unipolar) and in control subjects (n = 11) was studied; six of the acutely manic patients were reevaluated after a symptom-free interval of at least 6 months. The combined dexamethasone-suppression/human CRH-challenge test was used to probe HPA-system function. After CRH and dexamethasone pretreatment, ACTH and cortisol release were significantly increased in both manic and depressed patients in comparison to the control group. In the remitted patients with mania, a significant decrease in hormonal release after DEX and CRH was evident when compared to the acute manic episode, but the degree of CRH-stimulated hormone secretion in these remitted patients was still significantly larger than in normal controls. This study demonstrates that acute and remitted manic episodes are associated with a profoundly dysregulated HPA-system activity.
1. Current literature was searched to evaluate the use of magnetic resonance imaging in patients with bipolar disorder. 2. The presence of white matter hyperintensities, differences in temporal lobe and hippocampal structures, and ventricular enlargement in patients with bipolar disorder was assessed. 3. Further use of MRI in patients with bipolar disorder is reviewed.
Lithium is the most commonly used drug for the treatment of manic depressive illness. The precise mechanisms underlying its clinical efficacy remain unknown. We found that long-term exposure to lithium chloride dramatically protects cultured rat cerebellar, cerebral cortical, and hippocampal neurons against glutamate-induced excitotoxicity, which involves apoptosis mediated by N-methyl-D-aspartate (NMDA) receptors. This neuroprotection is long-lasting, occurs at therapeutically relevant concentrations of lithium with an EC50 of approximately 1.3 mM, and requires treatment for 6-7 days for complete protection to occur. In contrast, a 24-h treatment with lithium is ineffective. The protection in cerebellar neurons is specific for glutamate-induced excitotoxicity and can be attributed to inhibition of NMDA receptor-mediated calcium influx measured by 45Ca2+ uptake studies and fura-2 fluorescence microphotometry. The long-term effects of lithium are not caused by down-regulation of NMDA receptor subunit proteins and are unlikely related to its known ability to block inositol monophosphatase activity. Our results suggest that modulation of glutamate receptor hyperactivity represents at least part of the molecular mechanisms by which lithium alters brain function and exerts its clinical efficacy in the treatment for manic depressive illness. These actions of lithium also suggest that abnormality of glutamatergic neurotransmission as a pathogenic mechanism underlying bipolar illness warrants future investigation.
An unresolved question in neuroscience and psychology is how the brain monitors performance to regulate behavior. It has been proposed that the anterior cingulate cortex (ACC), on the medial surface of the frontal lobe, contributes to performance monitoring by detecting errors. In this study, event-related functional magnetic resonance imaging was used to examine ACC function. Results confirm that this region shows activity during erroneous responses. However, activity was also observed in the same region during correct responses under conditions of increased response competition. This suggests that the ACC detects conditions under which errors are likely to occur rather than errors themselves.
Imaging studies of patients with bipolar disorder demonstrate changes in deep white matter and subcortical gray nuclei that are seen as focal hyperintensities on T2-weighted magnetic resonance imaging (MRI). The objective of this study was to examine MRIs in a family with a strong history of bipolar disorder to look for possible MRI abnormalities in members with and without affective illness.
The authors obtained MRIs of 21 members of a family with a strong history of bipolar disorder. Eight of the family members studied had bipolar illness, one had symptoms of bipolar disorder but did not meet full DSM-III-R criteria, two had unipolar disorder, and 10 did not have bipolar disorder.
Fifteen of the 21 family members had MRI findings, including six of 10 family members who had no affective disorder and all of those with bipolar disorder. Lesions of both white matter and subcortical gray nuclei were found.
Although the clinical significance of these MRI findings is unknown, the high prevalence of MRI findings in both affected and unaffected family members suggests that MRI findings may potentially serve as a biological marker for bipolar disorder. Recent genetic studies have established a link between familial leukoencephalopathy and chromosome 19. If leukoencephalopathy appears to be related to bipolar disorder, it may allow clearer characterization of the genetics of the disorder.