1. Mood-stabilizing drugs: mechanisms of action
Robert J. Schloesser, Keri Martinowich, Husseini K. Manji 
Trends in Neurosciences 
Volume 35, Issue 1, Pages (January 2012)
DOI: /j.tins
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2. Figure 1
Roles of the hippocampal trisynaptic circuit in bipolar disorder and therapeutic mechanisms of mood-stabilizer action. (a) The trisynaptic circuit comprises the dentate gyrus (DG, blue), which is also the site of the subgranular zone (SGZ), one of the two germinal zones of the brain that retains ongoing neurogenesis throughout life. DG cells (green) are glutamatergic cells whose axons form the mossy fiber pathway, which projects into the CA3 regions. DG cells synapse onto both glutamatergic CA3 pyramidal cells as well as GABAergic interneurons that reside in CA3. CA3 pyramidal cells project axons that form the Schaffer collaterals, synapsing onto CA1 pyramidal cells. CA1 pyramidal cells provide the major output of the hippocampal circuit, which is to the subiculum. (b) Control of hippocampal output via the subiculum. The main output of the hippocampus is the subiculum, which in turn sends major projections to both cortical and subcortical targets. Projections to the medial prefrontal cortex (mPFC), amygdala, striatum and hypothalamus are of primary interest in relation to functional roles of the hippocampus in stress-related disorders and in mood-stabilizer treatment. (c) Mood stabilizer-induced changes in hippocampal strength and synaptic plasticity. Lithium increases presynaptic excitability as well as synaptic efficiency at hippocampal CA1 synapses, leading to enhancement of excitatory postsynaptic potentials [30–33]. The effects of lithium on synaptic enhancement at CA1 synapses may arise from its ability to potentiate currents through the AMPA subtype of ionotropic glutamate receptors by selectively increasing the probability of channel opening [34]. Lithium and valproate have documented effects on increasing levels of the neurotrophin brain-derived neurotrophic factor (BDNF) [43–47], which is also implicated in certain forms of long-term potentiation (LTP) at the CA3–CA1 synapse [52]. (d) Cellular remodeling in response to stress and mood-stabilizer treatment. Exposure to stress and excessive glucocorticoids leads to dendritic retraction and induction of apoptotic cell signaling [91]. Lithium treatment prevents and/or reverses stress-induced hippocampal dendritic atrophy of hippocampal principal cells [88]. In patients with bipolar disorder, volume is decreased in hippocampal subfields, whereas chronic lithium treatment leads to an increase [76–80]. (e) Effects of mood stabilizers on adult hippocampal neurogenesis and potential roles in therapeutic response. Adult neurogenesis encompasses the proliferation of progenitor cells as well as their subsequent differentiation, maturation and integration into the existing hippocampal circuitry. Newly born granule cells project axons into the hilus, where they synapse primarily with interneurons or into the CA3 subfield. Mood stabilizers have documented effects on increasing rates of adult neurogenesis [59–61]. Adult neurogenesis contributes to normal hippocampal function, including the ability of the hippocampus to provide negative feedback regulation over the HPA axis [64–66].
Trends in Neurosciences  , 36-46DOI: ( /j.tins )
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3. Figure 2
Neuroimaging studies in bipolar disorder. (a) Predicted volumetric changes in the hippocampus (i) and amygdala (ii) for healthy subjects, individuals with bipolar disorder not on lithium therapy, and individuals with bipolar disorder on lithium therapy, in an international collaborative mega-analysis of adult patient data [72]. Mean predicted volumes are presented from linear mixed models while adjusting for gender, research center and age. Highly significant differences between the three groups are present for both hippocampus (F=11.32, P=0.0001) and amygdala (F=8.904, P=0.0002). Individuals with bipolar disorder on lithium show greater volumes compared with both those not on lithium [hippocampus (F=9.53, P=0.002)] [amygdala (F=6.33, P=0.013)] and healthy subjects [hippocampus (F=12.96, P=0.0004)] [amygdala (F=10.97, P=0.001)]. Healthy subjects show greater mean volumes than individuals with bipolar disorder not on lithium [hippocampus (F=7.81, P=0.005)] [amygdala (F=5.13, P=0.024)]. (b) Cortical gray matter differences (GMD) as a function of lithium treatment. (i) Differences in gray matter volume in patients treated with lithium only (Li+; n=20) versus control subjects (n=28). Widespread areas of gray matter concentration can be observed across the cortex. Differences are particularly striking in the left cingulated and paralimbic association cortices and bilaterally in the visual association cortex. (ii) No significant differences were observed in this study in gray matter densities between patients who were not taking lithium (Li–; n=8) and control subjects. (c) Gray matter volume in the subgenual prefrontal cortex (PFC) [i.e. anterior cingulated cortex (ACC) ventral to the genu of the corpus callosum] was found to be abnormally reduced in patients with bipolar disorder or major depressive disorder (MDD) compared with control subjects [85]. Demonstration of this effect was made by acquisition of magnetic resonance imaging-based morphometric measures that were guided by positron emission tomography (PET) images showing a reduction of cerebral blood flow and glucose metabolism in the subgenual area of the PFC. Voxel by voxel analysis of neurophysiological data from depressed versus control subjects was used to localize the differential activity more specifically to the subgenual PFC. (d) Subgenual PFC volumes of patients with bipolar disorder or MDD are decreased compared with control subjects. However, bipolar individuals treated with lithium (Li) or valproic acid (VPA) are comparable to control subjects. (e) Lithium-induced volumetric changes. This table provides selected references that compare volumetric changes in response to lithium treatment in patients with bipolar disorder not on lithium treatment versus those on lithium therapy versus healthy controls. Meta-analyses are denoted in bold. Abbreviation: ROI, region of interest. Reproduced, with permission, from [76] (a), [82] (b) and [89] (c); modified, with permission, from [83] (d).
Trends in Neurosciences  , 36-46DOI: ( /j.tins )
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4. Figure 3
Prefrontal–limbic system circuitry important in mood disorders. Circuitry connecting key brain regions, including the prefrontal cortex, amygdala, hippocampus and hypothalamic–pituitary endocrine system, that are believed to be important in mood disorders and are probably targeted by mood-stabilizing drugs. (*) Basic functions of each individual region as well as (#) pertinent findings in mood disorders or mood-stabilizing drug mechanisms of action are described. Abbreviations: BD, bipolar disorder; CBF, cerebral blood flow; HPA, hypothalamic–pituitary–adrenal axis; MDD, major depressive disorder.
Trends in Neurosciences  , 36-46DOI: ( /j.tins )
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5. Figure I
The response to stress includes activation of the hypothalamic–pituitary–adrenal (HPA) axis. Activation of the HPA axis leads to corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) production in the paraventricular nucleus of the hypothalamus. These hormones are released into the bloodstream, leading to secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH stimulates the synthesis and release of glucocorticoids (cortisol in humans, corticosterone in rodents) from the adrenal cortex into the bloodstream. Cellular effects of glucocorticoids are mediated via glucocorticoid receptor (GRs) and mineralocorticoid receptor (MRs). Regulatory control over the HPA axis is mediated via negative feedback loops at the level of the pituitary as well as from other regions of the brain, including the hippocampus.
Trends in Neurosciences  , 36-46DOI: ( /j.tins )
Copyright © 2011 Elsevier Ltd Terms and Conditions