Mood-stabilizing drugs: mechanisms of action

Review

Special Issue: Neuropsychiatric Disorders

Mood-stabilizing drugs: mechanisms of action Robert J. Schloesser1, Keri Martinowich2 and Husseini K. Manji3 1

Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, MD, USA 3 Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA 2

Mood-stabilizing drugs are the most widely prescribed pharmacological treatments for bipolar disorder, a disease characterized by recurrent episodes of mania and depression. Despite extensive clinical utilization, significant questions concerning their mechanisms of action remain. In recent years, a diverse set of molecular and cellular targets of these drugs has been identified. Based on these findings, downstream effects on neural and synaptic plasticity within key circuits have been proposed. Here, we discuss recent data, identify current challenges impeding progress and define areas for future investigation. Further understanding of the primary targets and downstream levels of convergence of moodstabilizing drugs will guide development of novel therapeutic strategies and help translate discoveries into more effective treatments with less burdensome adverse-effect profiles. Introduction Significant questions remain in understanding the neurobiological mechanisms underlying bipolar disorder. Bipolar disorder pathophysiology is thought to arise from interactions between genetic risk factors and environmental influences, which include exposure to adverse childhood experiences, chronic stress and trauma. As with other major neuropsychiatric disorders, a neurodevelopmental component probably contributes to disease pathophysiology. A prominent theory suggests that bipolar disorder arises from alterations in neural and synaptic plasticity [1]. Neuroplastic changes that occur during critical developmental windows may contribute to structural and functional changes in key circuits, which can have long-lasting effects on adult brain function. Underlying deficits in plasticity may be aggravated or unmasked later in life by exposure to stressful events, a key risk factor in mood disorder development [2]. The theory that alterations in neural and synaptic plasticity contribute to disease pathology is supported by reports of structural and functional changes in both neuroimaging and postmortem studies of individuals with bipolar disorder [3]. The most important pharmacological treatments for patients with bipolar disorder are mood-stabilizing drugs, which comprise a diverse group of compounds, including Corresponding author: Manji, H.K. ([email protected]). Keywords: bipolar disorder; mood-stabilizing drugs; neurotrophic factors; synaptic plasticity; mania; lithium.

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lithium salts as well as the anticonvulsants valproate, carbamazepine and lamotrigine. All mood stabilizers ameliorate symptoms of mania and some (e.g. lithium and lamotrigine) have documented antidepressant properties [4–6]. Most importantly, mood stabilizers decrease episode recurrence (phase prophylaxis) and lithium decreases suicide risk [7] Use of lithium as a successful treatment for bipolar treatment was first published in 1949 [8], but did not gain US Food and Drug Administration approval until 1970. Several medications developed for other indications (e.g. anticonvulsants for epilepsy or antipsychotics for schizophrenia) were subsequently approved for bipolar disorder treatment, but no novel medications have been introduced specifically for bipolar disorder since the introduction of lithium over 60 years ago. By providing an efficacious treatment for millions of patients, lithium therapy was a significant breakthrough in neuropsychopharmacology. However, lithium monotherapy is often insufficient, and a majority of patients require combination therapy [9,10]. Approval of a variety of additional pharmacological treatments, including the anticonvulsants discussed above, as well as numerous atypical antipsychotic agents, has increased the chances of identifying a successful combination therapy. Despite these advances, current treatment options are less than adequate in treating many facets of the illness. In addition, many patients cannot tolerate the adverseeffect profiles of existing therapies (e.g. changes in weight and appetite, tremor, blurred vision, dizziness, etc.), leading to frequent medication changes and high rates of non-adherence [11]. Hence, there is a critical unmet need for new treatments with greater efficacy, faster onset and better tolerability. A more thorough understanding of bipolar disorder pathophysiology, as well as the molecular-, cellularand systems-level mechanisms mediating the effects of currently utilized treatments, will facilitate development of novel therapeutics. Overview of bipolar disorder Bipolar disorder is common, with approximately 1% of the population affected [12–14]. The disorder is characterized by the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV as severe bouts of recurring mania and depression. Up to 5% of the population falls under either the diagnostic category of bipolar II disorder [12], which is characterized by severe bouts of depression and hypomania, or a bipolar spectrum disorder, including cyclothymic

0166-2236/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2011.11.009 Trends in Neurosciences, January 2012, Vol. 35, No. 1

Review disorder. Although patients with bipolar disorder II have milder manic episodes (hypomania), their disease is not considered less serious. Cyclothymic disorder is characterized by less extreme mood fluctuations that range from mild depression to hypomania. Bipolar disorder is a major, worldwide health problem with devastating consequences for affected individuals, their families and society. The poor prognosis of these patients is illustrated by high rates of relapse, lingering residual symptoms, cognitive impairments and diminished quality of life [15,16]. Patients with bipolar disorder are prone to coexisting medical conditions, including cardiovascular disease, diabetes mellitus and thyroid dysfunction [17–20]. Underscoring severity, it is estimated that patients with bipolar disorder I have a 5– 17-fold higher suicide rate than the general population [21]. Symptoms of bipolar disorder I typically commence in young adulthood. Patients cycle between states of mania or depression interspersed with symptom-free intervals of variable length. Mania is characterized by increased irritability, hyperactivity, euphoric and/or delusional thinking, promiscuity, heightened risk-taking, decreased sleep, decreased need for sleep and, in some patients, is accompanied by psychosis. During depressive episodes, patients experience feelings of hopelessness, guilt, decreased libido, suicidal thoughts and decreased ability to experience reward and happiness. The process of switching between opposing mood states is a core feature of bipolar disorder, which uniquely distinguishes it from other neuropsychiatric disorders with which it shares many common symptoms (e.g. depressed mood, sleep disturbances, anxiety, and changes in weight and appetite) (Box 1). In addition to distinct periods of mania or depression, some patients experience mixed states. A subset of patients with either bipolar disorder I or II show rapid cycling, which is defined as more than four episodes of either mania or depression within 1 year. In untreated patients, the disease typically worsens owing to cycle acceleration; the frequency of episodes increases owing to shortening of the length of symptom-free intervals. Individuals in episode-free intervals were classically described as in restitutio ad integrum, but this view has been challenged in light of credible evidence that an increase in the number of episodes correlates with decreased cognitive abilities and deficits in social functioning. Mechanisms of action of mood-stabilizing drugs Synaptic plasticity and neurotransmission Historical perspectives postulated that mood disorders arise from ionic shifts and changes in membrane permeability, which led to direct impairments in neural excitability and transmission [13]. Given that lithium was one of the few options for successful treatment of bipolar disorder treatment, numerous studies investigated its effects on neurotransmitter chemistry. Early studies documented effects of lithium on many neurotransmitter and neuromodulator systems, including the monoaminergic, serotonergic, cholinergic and GABAergic systems [22– 24]. One of the prevailing hypotheses speculated that lithium interfered with the sodium–potassium electrogenic pump, and that the direct effects of this alteration on synaptic transmission led to the observed secondary effects in specific neurotransmitter systems [25,26].

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Box 1. The switch process in bipolar disorder The phenomenon of switching between the polarities of depression and mania or hypomania, singularly distinguishes bipolar disorder from other neuropsychiatric disorders. Hence, understanding this process is critical for a full understanding of bipolar disorder pathophysiology. Switching from a depressive to a manic state can occur spontaneously, but can also be influenced by exposure to stress and sleep deprivation as well as illicit drug use [125]. In addition, electroconvulsive therapy, antipsychotics and some antidepressant therapies can induce switching [125]. Individual genetics, especially in genes that regulate monoaminergic transmission and circadian rhythms, may also influence predisposition towards state switching [126,127]. Understanding these processes is important because individuals with patterns of switching have a poorer clinical outlook and carry greater risk for substance abuse and suicide [125,128,129]. Lack of knowledge about state switching has contributed to delays in research progress because the cyclic nature presents an extreme challenge for rodent modeling. Although considerable caution needs to be taken in applying animal models to complex neuropsychiatric disorders, they are invaluable tools for exploring underlying cellular and molecular biology. Most animal models that have been used for bipolar disorder research have focused on either mania or depression, rather than modeling both behaviors within the same individual [14]. Understanding the biology underlying the switch process could allow for modeling induction of different states, which would be an invaluable tool for the development of new therapeutics.

More recent evidence suggests that mood disorders, including bipolar disorder, affect intracellular signaling cascades that lead to impairments in structural and functional neural plasticity as well as alterations in glutamatergic neurotransmission [2,27]. Glutamate, the most abundant excitatory neurotransmitter, is integral for synaptic transmission in brain circuitry, and is a key regulator of synaptic strength and plasticity, which play major roles in the neurobiology of learning, memory and general cognition [28]. Altered glutamate levels in plasma, serum and cerebrospinal fluid have been observed in human studies of individuals with mood disorders [29]. Moreover, NMR spectroscopy studies have shown altered levels of glutamate and related metabolites in diverse brain regions of patients with bipolar disorder [29]. Accumulating evidence indicates that lithium has direct effects on glutamatergic neural transmission. In particular, several lines of evidence suggest that lithium alters neuronal excitability at hippocampal CA1 synapses, leading to enhanced excitatory postsynaptic potentials [30–33] (Figure 1a,c). The ability of lithium to enhance synaptic transmission in hippocampal CA1 has been attributed to an increase in presynaptic excitability as well as increases in synaptic efficiency. A recent report has also shown that its effect 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]. These effects on hippocampal synaptic transmission may be of particular relevance for mood disorder treatment because the hippocampus is a key component of the limbic system network, and is implicated in emotional regulation, cognition and memory. Hence, dysfunctional hippocampal signaling may contribute to behavioral disturbances in mood disorders, a hypothesis further supported by consistent findings of declarative memory deficits in patients with mood disorders [35–37]. As the last relay in the 37

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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].

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Review tripartite hippocampal circuit, alterations in synaptic plasticity in CA1 pyramidal neurons could effect changes in hippocampal and/or subicular modulation of several key target structures, including the prefrontal cortex (PFC), amygdala and striatum, as well as hippocampal control over hypothalamic endocrine regulation (Figure 1a,b). This is particularly interesting in light of prominent theories suggesting that dysfunction in the neural circuit linking the hippocampus, PFC and anterior cingulate cortex (ACC) are tightly linked to the affective and cognitive abnormalities seen in mood disorders [38] (Figure 3). Direct effects on neural transmission have also been documented for mood stabilizers classified as anticonvulsants. Valproate decreases high-frequency action potential firing by enhancing inactivation of voltage-gated sodium channels and indirectly enhances GABAergic function [39]. Lamotrigine blocks both voltage-gated sodium channels and L-type calcium channels, which can lead to substantial effects on baseline neurotransmission [40]. In addition, both valproate and lamotrigine upregulate excitatory amino acid transporter activity, leading to enhanced glutamate clearance [41,42]. Hence, these mood stabilizers may indirectly influence excitatory neurotransmission by modulating the rate of glutamate uptake. Intracellular signaling cascades Studies over the past 15 years have led to the hypothesis that mood disorders may not only be attributable to direct cellular impairments in neural excitability and transmission, but also to impairments in cellular signaling cascades that mediate structural and functional changes in neural and synaptic plasticity. Preclinical studies have pointed to deficits in intracellular signaling cascades associated with cell survival, growth and metabolism. As such, recent studies have attempted to identify common effects of chemically divergent mood stabilizers with the intent of elucidating functional targets of efficacious treatment response. Both preclinical and clinical studies have suggested that lithium exerts neurotrophic and neuroprotective effects, and recent research has identified specific roles for lithium in activating relevant intracellular signaling cascades. Lithium leads to upregulation of the neurotrophin, brain-derived neurotrophic factor (BDNF) [43–47] as well as the neuroprotective protein, B-cell lymphoma/leukemia-2 (Bcl2) [48,49]. It has been suggested that diminished levels of Bcl-2 contribute to findings of reduced hippocampal pyramidal cell size [50], and decreased levels of BDNF have been identified in bipolar disorder [51]. In addition to its neurotrophic effects, BDNF plays a key role in regulating synaptic plasticity and, in particular, is required for specific forms of long-term potentiation at the CA3–CA1 synapse (Figure 1c) [52]. Enhanced Bcl-2 expression counteracts deleterious effects of stress on neurons, suggesting that its pharmacological induction has utility in cases of compromised cellular resiliency. In addition to antagonizing cell-death signaling, Bcl-2 stimulates axonal regeneration following trauma [53]. At the cellular level, Bcl-2 plays a key role in controlling intracellular calcium dynamics, which is of special interest because impaired calcium signaling regulation has been repeatedly recognized as a cellular abnormality in bipolar disorder [54]. Interestingly, intracellular calcium signaling

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also plays an important regulatory role in synaptic plasticity cascades, including mediating activity-dependent transcription of BDNF [55]. A single nucleotide polymorphism in the Bcl-2 gene (rs956572) is associated with increased bipolar disorder risk, and is functionally linked to: (i) reduced Bcl-2 expression in human lymphoblasts; and (ii) decreased gray matter volume in the ventral striatum, an area implicated in the neurobiology of reward and emotional processing [56]. Further supporting a role for Bcl-2 function in bipolar disorder, this polymorphism significantly affects intracellular calcium homeostasis via regulation of endoplasmic reticulum release in lymphoblasts derived from patients with bipolar disorder [57,58]. Recent evidence, which may be relevant for the clinical effects of lithium, showed that it promotes neurite outgrowth and stimulates adult hippocampal neurogenesis in rodents [59–61]. Given that newborn neurons integrate into the existing circuitry, where they display enhanced plasticity in behaviorally relevant circuits [62,63], this could be significant for hippocampal function in mood regulation (Figure 1a,e). It has been reported that hippocampal neurogenesis contributes to negative feedback regulation of the hypothalamic–pituitary–adrenal (HPA) axis [64,65]. Supporting the view that newborn neurons may be involved in HPA axis feedback regulation, these cells contribute to the antidepressant-induced improvement in stress integration [66]. Thus, in a depressive state, facilitating hippocampal neurogenesis may restore proper control over the stress response system. This is particularly interesting because there is robust evidence of HPA axis abnormalities in bipolar disorder (discussed below). Several enzymes have been shown to be directly inhibited by lithium at therapeutically relevant concentrations [14]. These include inositol monophosphatase (IMPase); inositol polyphosphate a-phosphatase; bisphosphate 30 -nucleotidase; fructose 1,6-bisphophatase; glycogen synthase kinase 3 (GSK3) and phosphoglucomutase [67–69]. Evidence from numerous studies has also implicated protein kinase C (PKC) in bipolar disorder pathophysiology, and both lithium and valproate decrease PKC levels as well as PKC activity. Lithium interacts with the phosphoinositol–PKC pathway through inhibition of IMPase, which results in decreased free myo-inositol and production of diacylglycerol. These actions converge to result in decreased PKC levels and enzyme activity [70]. Valproate also results in decreased PKC levels and activity, but the mechanism by which it does so is distinct from that of lithium [71]. The reader is directed to other sources for a more thorough discussion of the extensive literatures on these topics [13,14]. Pinpointing levels of convergence Structure–function alterations in bipolar disorder and effects of mood stabilizers In vivo human studies reporting decreased gray matter volumes in bipolar disorder that are either attenuated or increased by lithium treatment have provided strong support for its neuroprotective and neurotrophic effects [72–86] (Figure 2). Although consistent evidence of decreased hippocampal volume was identified in major depressive disorder, initial studies suggested no differences in bipolar disorder [87]. However, using a fine-mapping 39

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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).

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three-dimensional technique, a recent study discerned structural abnormalities in patients with bipolar disorder that roughly correspond to the hippocampal CA1 subfields [79]. Several additional reports and meta-analyses have documented increased total hippocampal volume in patients treated with lithium compared with unmedicated patients [76–78,80]. In line with these findings, it is interesting that lithium treatment reverses hippocampal dendritic atrophy induced in an animal model of chronic stress [88] (Figure 1d). In a recent mega-analysis to systematically identify regional volumetric deficits and effects of lithium administration in bipolar disorder, pooled imaging data showed cerebral volume reductions that were significantly associated with illness duration. Individuals with bipolar disorder who were not on lithium therapy showed significant decrease in cerebral and hippocampal volumes, whereas patients treated with lithium showed significantly increased hippocampal and amygdala volumes [76]. Data on amygdala volumes in patients with bipolar disorder have been conflicting, but recent studies using high-resolution magnetic imaging resonance (MRI) have convincingly shown that amygdala volume is smaller in unmedicated patients with bipolar disorder and larger in patients with bipolar disorder on mood-stabilizer treatment [81].

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Together with data in the above-referenced mega-analysis, it appears that lithium does have trophic effects in the amygdala [76,81]. Prominent volumetric abnormalities have been reported in bipolar disorder in the ACC [83,89,90], and chronic treatment with lithium or valproic acid has been associated with increased gray matter volumes in this region [82,83]. Preclinical studies showing that lithium and valproate increase the expression of molecules involved in synaptic plasticity, cytoskeleton remodeling and cellular resilience may explain why these imaging studies have found increased volumes in patients with lithium-treated bipolar disorder [3,91]. Hence, the existent data point to neurotrophic and neuroprotective actions of lithium in multiple areas of the limbic and/or prefrontal network by increasing cellular resiliency, enhancing synaptic plasticity and modulating neuronal morphology. Functional neuroimaging studies have been invaluable in identifying putative misregulated brain circuits in mood disorders. Combined with data from structural and volumetric studies, researchers have identified key brain regions within limbic, striatal and PFC loops that are thought to underlie cognitive and behavioral manifestations. These regions include the amygdala and related limbic structures, ACC, orbital and medial PFCs, ventroAnterior cingulate cortex (∗) This region has extensive connections with brain structures implicated in the modulation of emotional behavior, and participates as part of this extended network in emotional processing and regulation of autonomic response (#) Reduction in gray matter volume in MDD and BD [89,90], although not seen in these studies [76,82], gray matter volumetric increases in patients with lithium-treated bipolar disorder [82,83], but not evidenced in this analysis [76], alterations in metabolic activity [3,89–90], decreased glial cell density [83,90], altered glutamate levels [29]

Medial prefrontal cortex (∗) Regulation of emotion and assessment of consequence in decision-making; extensive connections with limbic areas, including hippocampus and amygdala (#) Altered CBF and glucose metabolism in primary depression [3,90]

Orbifrontal cortex (∗) Integration of multi-modal stimuli and assessment of stimulus value and/or reward, extinction of unreinforced responses to stimuli [3,90] (#) Volume reductions, increased metabolism [90]

Hypothalamus–pituitary (∗) Links nervous system to endocrine system; synthesizes and secretes, neurohormones, including corticotropin-releasing hormone, an important Amygdala component of the stress system; key structure in controlling HPA axis function (∗) Evaluation of experience/stimuli (#) Hypercortisolemia, HPA axis abnormalities with strong emotional valence, acquisition and expression of emotionally related memories (#) Decreased volumes in patients with BD, with increased volumes in such patients on lithium treatment [76,78,81], elevated resting CBF and glucose metabolism [3,90]

Thalamus (∗) Sensory relay, extensive connections with limbic system and mood-related circuitry (#) Depressed individuals with MDD and BD show increased metabolism and CBF in the mediodorsal nucleus of the thalamus [3]

Hippocampus (∗) Learning, memory and cognition; site of ongoing adult neurogenesis; negative regulation over HPA axis (#) Reduction in gray matter volume in patients with BD, with increased volumes in such patients on lithium treatment [76–80]; decreased number of synapses and synaptic proteins; declarative memory deficits [35–37]

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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.

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Box 2. HPA axis and glucocorticoid receptor signaling in bipolar disorder The glucocorticoid cortisol, which is released from the adrenal gland, is the end product of the HPA axis, which comprises the hypothalamus, pituitary gland and adrenal cortices (Figure I). Neurosecretory cells within the paraventricular nucleus of the hypothalamus secrete corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the circulatory system of the pituitary. This causes release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary, which leads to cortisol release from the adrenals. Cortisol has numerous cellular effects, which are mediated via the GR and the mineralocorticoid receptor (MR). The hippocampus regulates the endocrine system stress system by modulating hypothalamic paraventricular nucleus activity. Chronic dysregulation of the HPA axis in response to stress is associated with impaired glucocorticoid function and inhibition of negative feedback via the GR [130]. Importantly, reduced levels of GR have been observed in patients with bipolar disorder or depression. Considerable evidence shows that stress exposure is associated with mood disorder development. Dysregulated HPA axis activation probably plays a key role in mood disorder development because stress-induced neuronal atrophy is prevented by adrenalectomy [99,100]. This is noteworthy given that a significant percentage of patients with mood disorders display some manifestations of HPA axis dysfunction, and patients with HPA axis dysfunction are most likely to be associated with volumetric reductions in the hippocampus [3,99,100]. A significant effect of long-term exposure to excessive glucocorticoids is a reduction in cellular resiliency, rendering neurons more vulnerable to other noxious insults, including excitotoxicity and oxidative stress [3,91,131]. Whether varying intracellular signaling cascades, particularly those associated with neuroprotective and neurotrophic signaling cascades, within the stress response system can provide resiliency or attenuate susceptibility to stressful stimuli remains an open question. Ongoing and future studies aimed at targeting BAG-1, which mediates GR trafficking, may help to determine whether these interventions can provide resiliency from GR-related stress effects [91].[]IG$FTD2)x_Bo( 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.

medial striatum, the medial thalamus and related regions of the basal ganglia [3,90] (Figure 3). As opposed to a localized lesion in an isolated region, disrupted signaling within interconnected circuits is thought to result in disease susceptibility and behavioral manifestation of mood disorder symptoms (see [3,90,92] for more details). Intersection with the glucocorticoid system and affective resilience Increasing evidence suggests that limbic system abnormalities intersect with disturbances in glucocorticoid signaling in mood disorders. Rates of hippocampal neurogenesis are negatively affected by increased levels of circulating glucocorticoids and chronic stress [93,94]. Conversely, recent evidence suggests that adult hippocampal neurogenesis plays a role in regulating the stress response system [64–66]. This is of considerable interest in light of: (i) the structural and volumetric deficits in the hippocampus of unmedicated patients with bipolar disorder (Figure 2); and (ii) the effects of lithium on hippocampal circuitry and 42

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neurogenesis (Figure 1c,d,e). Changes in HPA axis feedback regulation are one of the most robust biological abnormalities observed in affective disorders [95–98] (Box 2). Moreover, the subtypes of depression most frequently associated with HPA axis hyperactivation are the most likely to be associated with hippocampal volume reductions [99,100]. The functional importance of these disturbances is highlighted by studies showing that normalization of HPA axis activity parallels remission from depressive episodes and reduces relapse [101–104]. Furthermore, chronic treatment with lithium and valproate can enhance recovery from both the depressive and manic episodes associated with exogenous or endogenous (i.e. Cushing’s disease) elevations of glucocorticoids [91]. Importantly, it has been demonstrated that lithium and valproic acid (VPA) elevate levels of the bcl-2-associated athanogene, BAG-1, a cochaperone protein that inhibits glucocorticoid receptor (GR) activation [49]. Together, the available data suggest that interactions between GR and BAG1 counteract deleterious effects of hypercortisolemia in bipolar disorder and

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Box 3. Outstanding questions  What causes the observed volumetric loss in brains of patients with bipolar disorder, and how is lithium able to rescue these deficits? In brain areas of rodents that are homologous to regions where gray matter reductions have been observed (e.g. ventromedial PFC and hippocampus), exposure to stress results in dendritic atrophy and cell loss [91]. Significant dendritic atrophy would result in decreased neuropil volume, which accounts for a significant portion of gray matter volume. Studies of rodent models of chronic stress have suggested that similar processes of stress sensitivity and glucocorticoid excess underlie the gray matter volume reductions observed in patients [91]. Other hypotheses have pointed to a role for abnormal mitochondrial signaling and oxidative stress leading to apoptotic processes that ultimately result in cell death [131]. The ability of lithium treatment to increase levels of bcl-2 and BDNF may counteract or reverse the early stages of apoptotic cell signaling in the brains of patients with bipolar disorder.  What are the key biological mechanisms underlying the antimanic and mood-stabilizing effects of diverse mood-stabilizing agents? Can more efficacious and selective drugs be developed, with fewer adverse effects? As discussed in the main text, at least some of the therapeutic effects of mood-stabilizing drugs appear to be induced by activating neurotrophic and neuroprotective pathways, and related intracellular signaling pathways. However, it remains a challenge to make causal associations between these signaling pathways, which have been identified in animal and cell culture models, and therapeutic effects observed in patients. Increased access to patient samples, including postmortem human data, genome-wide association studies of bipolar disorder and treatment response groups, new methods of utilizing patient material [i.e. neurons derived from induced pluripotent stem cells (iPSCs)] and

contribute to affective resilience [91]. As such, treatments aimed at direct modulation of this pathway are the focus of considerable research interest [105], and efforts to identify therapeutics that enhance hippocampal neurogenesis may have utility in promoting glucocorticoid-related affective resilience. The findings pertaining to glucocorticoid regulation are particularly noteworthy because: (i) glucocorticoids represent one of the few agents capable of inducing both manic and depressive episodes in susceptible individuals; and (ii) glucocorticoids play important roles in mediating the stress response as well as modulating cellular and affective resilience (reviewed in [91]). New strategies and novel therapeutics A major treatment goal is prophylaxis, decreasing the episode severity and increasing the inter-episode interval. Despite treatment, a significant number of patients experience recurrent episodes. The onset of crippling depressions is particularly troublesome because administration of most currently utilized therapeutics have a lag time to achieve efficacy; only a fraction of patients meet response criteria by the end of the first treatment week [106–108]. This leaves patients highly vulnerable to self-harm and suicide, which is reflected by high rates of mortality during this latency period [109,110]. Thus, it is encouraging that recent studies have demonstrated that glutamatergic modulators and brain stimulation paradigms may hold promise as fast-acting therapeutics [109,111]. Glutamatergic modulators Growing appreciation of abnormal glutamatergic signaling in mood disorder pathophysiology has pointed

the ability to cross-integrate these data, will help in testing hypotheses of mood-stabilizer mechanisms of action.  Can neurophysiological or blood and/or peripheral tissue biomarkers be identified to measure or predict treatment response objectively? Biomarkers that can reliably aid in diagnosis or indicate successful treatment response are not yet available for bipolar disorder. The advent and decreasing relative cost of applying new molecular biology and proteomic techniques, genome-wide sequencing and functional neuroimaging should aid in the identification of biomarkers for diagnosis, as well as in personalized medicine and treatment with pharmacogenomics. The use of patient lymphoblasts and iPSCs may allow investigation of the putative signaling pathways discussed here (i.e. energy metabolism and mitochondrial signaling, GSK3 signaling, BDNF, Bcl-2 and calcium signaling), especially in conjunction with genetic risk alleles that have been identified for bipolar disorder [132,133].  Can better animal models be developed? Although considerable caution needs to be taken in applying animal models to complex neuropsychiatric disorders, they can be invaluable tools for understanding the underlying pathologies and, hence, for developing better treatments. An ideal model for bipolar disorder would include oscillations between depressive-like and manic behaviors and would be responsive to mood-stabilizer treatments. The progressive and cyclic nature of bipolar disorder presents an incredible challenge for modeling in rodents. Indeed, most models have tended to focus on modeling either mania or depression, with the majority focusing on stress-related depression [14]. However, as discussed in Box 1, understanding the nature of this switch phenomenon may be central to understanding the disorder and for the development of better treatments.

to glutamatergic modulators as promising areas for research development. As such, compounds targeting glutamate release, ionotropic glutamate receptors and glutamate transporters are under study. Initial studies identifying fast-acting antidepressant properties for ketamine, a non-competitive, high-affinity NMDA receptor antagonist, generated significant interest. In vitro, ketamine increases glutamatergic neuron firing rate and presynaptic glutamate release [112], effects that are thought to contribute to its robust and rapid antidepressive effects [111]. Adding substantial proof-of-concept validation to earlier clinical studies [113–115], a recent double-blind placebo controlled study on patients with treatment-resistant bipolar disorder replicated the robust, fast-acting antidepressant response of ketamine [115]. Preclinical studies have suggested that the antidepressant effects of ketamine are mediated by enhanced AMPA receptor activity. Enhanced glutamatergic signaling via AMPA receptors is thought to occur as a result of increased extracellular glutamate, which preferentially favors signaling via AMPA receptors owing to NMDA receptor blockade [112,116]. Subsequent studies in rodents have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway [117] is involved in mediating the fastacting antidepressant effects of ketamine, and this is dependent on rapid translation of BDNF via deactivation of the eukaryotic elongation factor 2 (eEF2) [118] (see also [119] in this Issue). Despite these encouraging results, long-term efficacy and safety remain to be addressed. A full elucidation of the molecular and cellular mechanisms that underlie the ability of ketamine to mediate both fastacting and sustained antidepressive effects is expected to 43

Review be valuable in advancing rational drug development for future antidepressant agents. Brain stimulation Recent strides in understanding the misregulation of critical neural circuits have raised the prospect of direct, therapeutic targeting by using brain stimulation to promote in vivo neural plasticity. Non-invasive methods, including transcranial magnetic stimulation and transcranial direct current stimulation, as well as an invasive form of deep brain stimulation (DBS) that targets brain areas via implanted electrodes, have been proposed [120]. In theory, this stimulation could elicit circuit-level modifications that can improve symptoms. The application of DBS as a successful therapy in Parkinson’s disease [121,122] has led to increased interest in its potential utility for treatment of severe mood disorders [121,122]. Functional neuroimaging data coupled with previous lesion data in rodents have been used to identify putative target regions and neural circuits that are associated with mood disorders, and exciting preliminary studies targeting the limbic–cortical circuit have shown promise in ameliorating symptoms in treatmentresistant depression [123,124]. Concluding remarks A growing body of evidence suggests that neuroplastic changes at the structural, functional and cellular levels underlie the misregulation of key circuits that contribute to bipolar disorder. Changes at the cellular and circuit level include impairments in neurotrophic and neuroprotective signaling cascades, altered glutamatergic and glucocorticoid signaling and changes in the rates of adult neurogenesis. Although several novel interventions and therapies aimed at targeting neural plasticity and cellular resilience have been identified, many issues remain (Box 3). The development of novel mood stabilizers with faster onset of action, increased efficacy and less burdensome adverse-effect profiles, would have enormous impact on public health and, as such, it is a priority to move both basic and clinical studies forward. Vertical movement will require closer interaction between basic and clinical researchers to identify targets of neural and synaptic plasticity that can be used in developing interventions and therapeutics in mood disorders. A better understanding of mechanisms ranging from molecules to synapses, to circuits and finally to behavior, will be required to achieve this goal. Disclosure statement H.K.M. is a paid employee of Johnson&Johnson Pharmaceutical Research and Development. Acknowledgements Support was provided by the National Institute of Mental Health Intramural Research Program. The figures and illustrations were designed and created by Anne K. Schlo¨sser.

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