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Molecular Psychiatry (2009) 14, 833–846 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp

FEATURE REVIEW

Neurobiological trait abnormalities in bipolar disorder C Langan and C McDonald Department of Psychiatry, Clinical Science Institute, National University of Ireland Galway, Galway, Ireland Dissecting trait neurobiological abnormalities in bipolar disorder (BD) from those characterizing episodes of mood disturbance will help elucidate the aetiopathogenesis of the illness. This selective review highlights the immunological, neuroendocrinological, molecular biological and neuroimaging abnormalities characteristic of BD, with a focus on those likely to reflect trait abnormalities by virtue of their presence in euthymic patients or in unaffected relatives of patients at high genetic liability for illness. Trait neurobiological abnormalities of BD include heightened pro-inflammatory function and hypothalamic–pituitary–adrenal axis dysfunction. Dysfunction in the intracellular signal transduction pathway is indicated by elevated protein kinase A activity and altered intracellular calcium signalling. Consistent neuroimaging abnormalities include the presence of ventricular enlargement and white matter abnormalities in patients with BD, which may represent intermediate phenotypes of illness. In addition, spectroscopy studies indicate reduced prefrontal cerebral N-acetylaspartate and phosphomonoester concentrations. Functional neuroimaging studies of euthymic patients implicate inherently impaired neural networks subserving emotional regulation, including anterior limbic, ventral and dorsal prefrontal regions. Despite heterogeneous samples and conflicting findings pervading the literature, there is accumulating evidence for the existence of neurobiological trait abnormalities in BD at various scales of investigation. The aetiopathogenesis of BD will be better elucidated by future clinical research studies, which investigate larger and more homogenous samples and employ a longitudinal design to dissect neurobiological abnormalities that are underlying traits of the illness from those related to episodes of mood exacerbation or pharmacological treatment. Molecular Psychiatry (2009) 14, 833–846; doi:10.1038/mp.2009.39; published online 19 May 2009 Keywords: bipolar disorder; neurobiology; neurotrophins; magnetic resonance imaging; positron emission tomography

Introduction Bipolar disorder (BD) is an illness of high heritability characterized by recurrent episodes of elation and depression, with interspersed periods of relatively normal mood. There has been a wide array of research studies into neurobiological abnormalities associated with BD in recent years incorporating diverse levels of scale and investigative techniques from intracellular signalling processes through to neuroimaging of neural networks. These have revealed marked heterogeneity of many neurobiological abnormalities described to date. This is most likely contributed to by the varying mood state of patients when assessed, the use of cross-sectional study designs and the examination of relatively small samples of patients. In an effort to distil out those neurobiological abnormalities, which are likely to be underlying trait features of the disorder, some research groups have specifically examined samples of patients during euthymia or Correspondence: Dr C Langan, Department of Psychiatry, Clinical Science Institute, National University of Ireland, Galway, Ireland. E-mail: [email protected] Received 18 December 2007; revised 8 January 2009; accepted 16 April 2009; published online 19 May 2009

remission. An allied research design that seeks to identify those trait abnormalities related to underlying susceptibility genes for the illness (that is, intermediate phenotypes) is to assess unaffected individuals genetically liable for BD, such as firstdegree relatives of patients or co-twins. Any such abnormalities cannot be because of the effects of medication or illness course, which might contribute to neurobiological abnormalities identified in euthymic patients. Identifying intermediate phenotypes could assist in elucidating the pathways from genotypic variation to the clinical syndrome of BD.1 Alternatively, the identification of neurobiological abnormalities, which vary with mood state, best identified through longitudinal study designs, may help clarify the pathophysiology of affective episodes and serve as markers to assess the impact of therapeutic interventions. This selective review provides an overview of the neurobiological trait abnormalities characteristic of BD in the fields of immunology, neuroendocrinology, molecular biology and neuroimaging. The review focuses on research that has sought to identify the fundamental trait-related abnormalities as indicated by their detection in adult patients with confirmed

Neurobiological trait abnormalities in BD C Langan and C McDonald

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euthymia, across all phases of the illness or in unaffected genetically liable subjects. The neuropsychological abnormalities persisting through euthymic BD or characteristic of those at genetic risk are reviewed in detail elsewhere.2–5

Immunology and neuroendocrinology The immune and neuroendocrine systems enable successful recovery from infectious or inflammatory processes by recognizing and eliminating foreign antigens, regulating inflammatory processes, coordinating tissue repair and remodelling, and ensuring that the altered metabolic demands of the host are adequately met.6 Cytokines and related secretory products from immune cells communicate with the endocrine and central nervous system to modulate their collective functions.7 Cytokines Cytokines are large polypeptide mediators (8–60 kDa) that regulate growth, differentiation and function of many cell types.8 Cytokines can be classed as proinflammatory, such as interleukin-1 (IL-1), IL-6, IL-8 and tumour necrosis factor, or anti-inflammatory, such as IL-2, IL-4, IL-10 and IL-13.9 Cytokines have been implicated in depressive disorder through the manifestation of profound depressive symptoms in patients receiving interferon treatment,10 activation of the inflammatory response in depression,11,12 identification of potent negative immunoregulatory effects of antidepressants13 and findings of abnormal cutaneous glucocorticoid receptor function in antidepressant-resistant patients.14 A number of studies have assessed the extent to which cytokine function differs from control samples in the differing mood phases of BD. Trait-related heightened pro-inflammatory function in BD is supported by evidence for increased numbers of circulating activated T cells and soluble IL-2 receptors in a cross-sectional controlled study of bipolar patients across all phases of the illness, which persisted at 2-year longitudinal follow-up.15 There are also reports of increased cell-mediated immunity activation in manic bipolar patients that persist into remission16 and increased production of the same pro-inflammatory cytokines (IL-8 and tumour necrosis factor-a) in both manic and depressed bipolar patients.17 Increased pro-inflammatory (IL-6 and tumour necrosis factor-a) and reduced anti-inflammatory (IL-4) cytokine levels have been reported in unmedicated manic patients compared with healthy controls, with some normalization of pro-inflammatory function longitudinally after mood-stabilizing treatment,18 indicating partial reversal of the proinflammatory state. Lithium therapy appears to reduce the number of cytokine-secreting cells, further supporting the anti-inflammatory potential of mood stabilizers.19 Heightened pro-inflammatory function is not specific to BD and has also been identified in patients Molecular Psychiatry

with schizophrenia and with major depressive disorders when compared with healthy controls,20 with normalization post-neuroleptic treatment.21 In summary, there is evidence for trait-based proinflammatory processes operating in BD by virtue of increased pro-inflammatory cytokine production across all phases of illness including remission, although acute exacerbation appears to be associated with an accentuation of this pro-inflammatory state and successful treatment with a partial reversal. Hypothalamic–pituitary–adrenal axis Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis in mood disorders is evident from hypersecretion of cortisol in unipolar depression22 and from the failure of depressed patients to suppress secretion of cortisol with the dexamethasone suppression test.23 The more sensitive combined dexamethasone suppression test and Corticotrophin-Releasing Hormone (CRH) challenge test (DEX/CRH)24 has enabled superior detection of impaired central glucocorticoid receptor signalling in patients with depression and BD compared with their healthy counterparts,25 findings that have been replicated to a lesser extent across a broad range of psychiatric illnesses. HPA axis dysfunction in affective disorders may well arise from decreased function or expression of brain glucocorticoid receptors, resulting in glucocorticoid resistance and subsequent elevation of circulating cortisol as a compensatory mechanism.26 Healthy first-degree relatives of depressed patients also display impaired glucocorticoid receptor signalling after DEX/CRH administration, suggesting that glucocorticoid dysfunction may be a familial trait marker for affective disorder.27 Evidence for trait-related HPA axis dysfunction in BD using the combined DEX/CRH test is shown by the consistently enhanced cortisol response in patients with acute mania or bipolar depression when compared with controls that persist on a longitudinal follow-up of up to 6 months’ remission.28–30 Interestingly, glucocorticoid receptor dysfunction, as measured by the dexamethasone suppression test, correlates with declarative and working memory deficits in euthymic BD patients, suggesting that trait-related glucocorticoid receptor dysfunction may be aetiologically linked to the cognitive dysfunction frequently reported even in remitted BD.31 Combined immunological and endocrinological investigations have also revealed the presence of Tcell steroid resistance as a potential trait marker in BD.32 Similar findings in major depressive disorder,33 and schizophrenia,34,35 suggest that such HPA axis dysfunction may represent a trait marker across the broader affective and psychotic disorder spectrum. In summary, the well-recognized HPA axis dysfunction and associated glucocorticoid resistance, which characterizes unipolar depression, is likely to reflect a trait-related abnormality in BD, given its presence across different phases of the illness, including remission. This may reflect the action of


susceptibility genes for the illness, as it has been reported in genetically liable unaffected subjects who have first-degree relatives with depression and with BD.

Molecular biology Intracellular signal transduction pathways in the central nervous system are uniquely responsible for coordinating the cellular response to information impinging on the cell from multiple sources and time frames. There has been considerable interest in the role that some of these pathways and their individual components may play in the pathogenesis of BD, including the cyclic adenosine monophosphate (cAMP)-generating pathway, the role of G-proteins, the phosphoinositide pathway, intracellular calcium signalling and the subsequent regulation of gene expression by these pathways. cAMP, PKA and BDNF The cAMP-generating pathway, as outlined in Figure 1, is activated by the binding of a neurotransmitter to the G-protein-coupled transmembrane receptor, inducing a conformational change in the G-protein, stimulation of adenyl cyclase and ultimately the conversion of adenosine triphosphate to cAMP. cAMP regulates many cellular functions, including metabolism and gene transcription, through the activation of protein kinase A (PKA). Activated PKA

γ

β

(+) AC (-) αi

αs

ATP

γ β

cAMP PKA

Activation of other signaling pathways

CREB Gene transcription (BDNF/bcl-2)

Long-term changes in neuronal plasticity and function

Figure 1 Cyclic AMP signalling pathway. The effects of cAMP are mediated largely by the activation of protein kinase A (PKA). One major downstream target of PKA is CREB (cAMP-response element-binding protein). After activation, phosphorylated CREB binds to the cAMP response element (CRE), a gene sequence found in the promoter of certain genes (including BDNF); antidepressants and also mood-stabilising drugs may activate CREB, thereby bringing about increased expression of BDNF. Modified and reproduced with permission from Molecular Psychiatry (2004) 9: 756–776. doi:10.1038/sj.mp.4001521.

phosphorylates other protein substrates, including cAMP-response element-binding protein (CREB), a transcription factor that provides a critical link between signal transduction and the expression of potentially relevant target genes, including the neuroprotective brain-derived neurotrophic factor (BDNF).36 There is a body of evidence linking unipolar depression with reduced serum BDNF levels, which normalize with antidepressant treatment.37–39 Both unmedicated euthymic and depressed bipolar patients have significantly higher cAMP-stimulated PKA activity than controls.40 Furthermore, whereas depressed or manic patients with BD show increased levels of the PKA catalytic subunit compared with euthymic patients or controls, all bipolar patients, regardless of mood phase, have increased levels of Rap1 (a protein substrate of PKA that has a role in regulating cell adhesion) compared with controls.41 Euthymic bipolar patients are reported to have increased PKA activity and reduced cAMP binding compared with controls, but without any corresponding difference in BDNF levels.42 Measurement of cAMP signalling system activity during PKA activation/inhibition in euthymic bipolar patients revealed increased basal PKA activity, increased PKA catalytic subunit levels and increased pCREB expression in bipolar patients compared with controls.43 However, inhibition of PKA resulted in decreased downstream BDNF expression specifically in the bipolar group, which implies an underlying trait-related defect in BDNF expression with compensatory upregulation of cAMP signalling to normalize BDNF levels in BD. There are conflicting results regarding serum BDNF levels in euthymic BD, with reduced serum BDNF levels reported,44 but other studies showing staterelated BDNF abnormalities in BD.45,46 A comparative study of patients with BD or chronic schizophrenia showed elevated BDNF levels in chronic schizophrenia compared with euthymic BD or healthy controls, interpreted by the authors as reflecting the impact of medication or lengthy course of schizophrenic illness.47 A longitudinal 1-year follow-up of patients with first-episode schizophrenia or BD showed lowered BDNF levels, which progressively increased to healthy control level at 1-year follow-up,48 which supports the hypothesis that abnormal BDNF levels are state related in affective and psychotic disorders. Thus, there is some evidence to suggest increased PKA activity as a trait feature of BD, with preliminary support for trait-related increased Rap1 levels. Although BDNF levels vary with episodes of illness and their treatment, it remains unclear whether some persistent BDNF reduction represents a BD trait.

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G-proteins G-proteins provide a link between neurotransmitter binding and subsequent signal transduction cascades. Studies in BD have shown increased levels of G-protein-a subunits across all phases of the illness, Molecular Psychiatry


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including unmedicated bipolar depression,49 unmedicated mania50 and lithium-treated euthymic bipolar patients,50,51 suggesting a trait-related G-protein subunit abnormality in BD, although state-related abnormalities have also been reported.52–54 There is also evidence that increased receptor–G-protein coupling in unmedicated manic bipolar patients normalizes subsequent to lithium or valproic acid therapy.55 This disagreement in the literature is most likely fuelled by heterogeneous samples and differing methods of G-protein quantification, including different G-protein subunits and measurement in leukocytes or platelets. The weight of current evidence suggests that G-protein abnormalities in BD are state related, with limited longitudinal data suggesting normalization of levels following treatment with mood stabilizers. Phosphoinositide pathway Activation of the phosphoinositide second messenger system by neurotransmitter/G-protein binding results in activated phospholipase C, hydrolysis of phosphatidylinositol 4,5-bisphosphate and creation of second messengers, such as 1,2-diacylglycerol and inositol 1,4,5-triphosphate (IP3). 1,2-Diacylglycerol activates the PKC system, whereas IP3 stimulates calcium release from smooth endoplasmic reticulum.56 Cross-sectional studies of platelet membrane phospholipids imply state-related abnormalities in phosphatidylinositol 4,5-bisphosphate levels and PKC activity in BD compared with controls.57–59 Euthymic bipolar patients taking lithium do display reduced phosphatidylinositol 4,5-bisphosphate levels compared with controls;60,61 however, this is most likely through mechanisms of inositol depletion62 and inositol monophosphatase inhibition by lithium.63 Intracellular calcium signalling In addition to their role in synaptic transmission and neurotransmitter release, calcium ions are involved in the mediation of more diverse cellular events, including synaptic plasticity, cell survival, exocytosis and cell death. Intracellular calcium signalling and homoeostasis are regulated in a complex manner that includes extracellular entry, release from intracellular stores, specific uptake into organelles and binding to particular proteins.64 Elevated basal calcium concentrations have been detected in transformed B lymphoblasts in bipolar I disorder compared with those in bipolar II disorder, major depression or healthy controls,65 associated with abnormalities in receptor-coupled and G-protein-coupled adenylyl cyclase activity.66,67 Increased total serum and ionized calcium has been reported in euthymic lithium-treated patients compared with healthy controls.68 Increased free intracellular calcium ion concentrations have been reported in both depression and mania.69 Lower basal intracellular calcium values have also been shown in the olfactory receptor neurons of euthymic bipolar patients

Molecular Psychiatry

compared with healthy controls.70 Thus, calcium homoeostasis appears altered across all mood states in BD. Mechanisms for this are hypothesized to include abnormalities in store-operated calcium channels, endoplasmic reticulum and mitochondria.71 Interestingly, post-mortem research has identified significantly decreased levels of mRNA coding for mitochondrial proteins and reduced expression of genes regulating oxidative phosphorylation and proteosome degradation in the hippocampus of BD patients compared with schizophrenia or controls.72

Neuroimaging Several neuroimaging studies have attempted to identify neuroanatomical, neurochemical or neurophysiological abnormalities associated with BD, although heterogeneity of patient samples has resulted in considerable inconsistencies in the literature. One might expect neuroanatomical abnormalities in particular to vary little across different clinical phases of illness; however, limited longitudinal data exist to confirm this assertion. Structural neuroimaging Most published structural neuroimaging studies of adult BD have been performed on heterogeneous samples of patients with respect to mood state, familial subtype, illness subtype, medication status, co-morbid alcohol/substance abuse and magnetic resonance imaging (MRI) analysis. Region-of-interest studies have largely focused either upon global tissue volumes or upon measurements of limbic or prefrontal structures because of the apparent involvement of these regions in mood regulation. Early computerized tomography imaging studies of bipolar patients indicated that the disorder was associated with enlarged ventricle-to-brain ratio, albeit to a lesser extent than that found in schizophrenia.73,74 Region-of-interest studies using MRI have largely confirmed, including by metaanalysis,75,76 that BD is associated with enlargement of the lateral ventricles. In contrast to schizophrenia and major depression, no overall difference has been found in whole-brain volume or in hippocampal volume between BD patients, in any phase of the illness, and controls.75,77–81 Studies that have examined amygdala volume have produced particularly conflicting findings, with some reporting amygdala enlargement in BD,82–85 whereas others report amygdala volume reduction.86–88 There is some evidence for reduced volume of specific prefrontal subregions in BD.89 Significant interest has been focused upon the subgenual prefrontal cortex because of its key role in mood regulation, but again results are conflicting with studies reporting reduced volume of this structure,90,91 and no difference.92,93 Studies using exploratory automated MRI analysis techniques, such as voxel-based morphometry, have


equally produced variable findings. A range of regional grey matter deficits has been reported, involving the thalamus,94 cingulate,95,96 temporal,95,97 parietal95,98 and prefrontal cortex,96 as well as grey matter excesses in fronto-parietal,99 thalamus,100 anterior cingulate98,101 and prefrontal cortices.98 Other computational morphometry studies report no grey matter abnormalities.102,103 Interestingly, there is accumulating evidence that lithium and other mood-stabilizing medications may increase grey matter volume,76,104,105 possibly through neurotrophic effects. Specific increases in grey matter volume following lithium treatment in bipolar patients have been reported in the hippocampus,106–109 bilateral cingulate and paralimbic cortices,101 and medial temporal lobe.110 Prefrontal grey matter increase has also been reported in lithium-treated healthy volunteers.111 Preliminary neuroimaging findings also suggest a neurotrophic effect for valproate and quetiapine.112 Thus, variable structural MRI results from studies incorporating remitted patients may be related to differential use of mood-stabilizing agents. One of the most consistent structural MRI abnormalities reported in BD is that of increased rates of deep white matter hyperintensities, qualitatively rated from T2-weighted or FLAIR sequence MRI scans.113,114 These are found with normal ageing and in association with vascular disease, but have been consistently reported at higher frequency in BD, even in young patients.115 A more detailed analysis of deep white matter changes in BD has been facilitated by application of diffusion tensor imaging, which can be used to detect microstructural abnormalities in myelinated tracts. Diffusion tensor imaging studies have largely reported disturbance of white matter microstructure in BD, particularly affecting the prefrontal regions.116–120 Findings from MRI studies of clinically screened euthymic BD patients include significantly reduced cortical grey matter, reduced cerebral white matter and increased ventricular and sulcal CSF compared with matched controls,121 and reduced temporal lobe volumes bilaterally.122 Assessment of white matter integrity between the subgenual cingulate and the amygdalo-hippocampal complex in euthymic bipolar patients revealed an increased number of reconstructed white matter fibres in this tract on the left side compared with that in controls, interpreted by the authors as consistent with lateralized ventral– limbic system dysregulation in BD.123 In addition to the apparently variable effects of medication on regional brain structure, abnormalities detected during euthymia may be related to chronicity effects after several episodes of illness or other confounds of having the illness, such as alcohol/ substance abuse. MRI studies that include unaffected relatives of bipolar patients may assist the identification of bipolar endophenotypic traits by avoiding the confounding effects of illness-related factors on brain structure. Such studies have reported a high pre-

valence of deep white matter hyperintensities in unaffected relatives of patients with BD from densely affected families,124 decreased left hemispheric white matter in unaffected co-twins from twin pairs discordant for BD125 and reduced anterior thalamic grey matter in unaffected relatives of patients with BD.94 McDonald et al.126 reported grey matter deficits in the right anterior cingulate and ventral striatum, and distributed white matter deficits in bilateral frontal, left temporoparietal, right parietal regions and anterior corpus callosum in association with increasing genetic liability for BD in a sample of multiply affected BD families. In summary, there is extensive heterogeneity among structural imaging studies of BD. The most consistent findings are of ventricular enlargement and increased rates of deep white matter hyperintensities, as outlined in Table 1. Structural abnormalities in prefrontal and limbic regions are regularly reported but lack consistency to date, most likely contributed to by heterogeneous clinical samples and the varying effects of mood-stabilizing medications on brain structure. Studies focused upon clinically confirmed euthymic individuals have detected grey and white matter deficits. Considerable evidence is accumulating for trait-related white matter abnormalities in the disorder, which may also reflect genetic liability as they are found early in the course of illness and in genetically liable unaffected relatives of patients with BD.

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Magnetic resonance spectroscopy Magnetic resonance spectroscopy (MRS) is a useful technique for investigating the activity of neurochemical compounds in regions of the brain. The most commonly used technique involves the use of proton (1H) MRS to measure the concentration of N-acetylaspartate (NAA), creatine and phosphocreatine (Cr þ PCr), choline-containing compounds (Cho) and myo-inositol (Ino). Phosphorus (31P) MRS has also been used to assess aspects of cellular metabolism. Proton MRS Several proton MRS studies have been completed using small numbers of patients in varying mood states,127 with reports of reduced cerebral NAA in the dorsolateral prefrontal cortex, anterior cingulate and hippocampal regions, potentially indicative of neuronal cell loss127 or mitochondrial dysfunction.128 Several of these studies were performed on predominantly euthymic patients127 and therefore indicate trait-related abnormalities in NAA, which appears prominent in the hippocampal region.129 NAA levels may be increased or normalized by lithium treatment,130,131 with valproate and quetiapine also reported to modulate NAA/choline ratios.136 Significantly elevated concentrations of choline, suggestive of impaired phospholipid metabolism and breakdown, are reported especially in the basal ganglia of depressed and euthymic BD patients, Molecular Psychiatry


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Table 1

Summary of neurobiological trait abnormalities in bipolar disorder

Field of research

Findings

References

Immunology

Increased numbers of activated T-cells Increased numbers of sIL-2R Increased cell-mediated immunity Increased production of pro-inflammatory cytokines Increased ACTH and cortisol release Glucocorticoid resistance Increased PKA activity Altered intracellular calcium signalling Reduced serum BDNF levels Increased levels of G-protein a-subunits Enlargement of lateral ventricles White matter abnormalities Volumetric abnormalities of amygdala Temporo-parietal and cortical grey matter deficits Reduced volume of subgenual prefrontal cortex Volumetric abnormalities of thalamus Enlargement of basal ganglia Reduced hippocampal and cerebral NAA Raised choline levels Reduced PME levels Reduced orbitofrontal and ventral prefrontal cortex activity

15

Altered dorsal anterior cingulate activity Impaired DLPFC activation

139,140,159

Increased activation of anterior limbic regions, temporal and parietal cortices and cingulate during cognitive or affective tasks

144,148–150,161–166

HPA axis Molecular Biology Structural neuroimaging

MRS Functional neuroimaging

15 16 17,18 28–30 32 40–43 65,70–72 44–48 49–55 75 113–120,122,123,125,126 82–88 95,98,99,102,103,121 90–93,95,96,98,101–103 75,94,100,102,103,122 85 127,129 132,133 137,154,155 139,142,143

158

Strength of evidence as a trait marker þ þ þ þþ þþ þ þ þ þ / þ / þþ þþ þ / þ / þ / þ / þ / þþ þ þ þ þ / þ / þ /

Abbreviations: BDNF, brain-derived neurotrophic factor; MRS, magnetic resonance spectroscopy; NAA, N-acetylaspartate; PKA, protein kinase A; PME, phosphomonoester. þ þ : Strong evidence to support finding as a trait marker; þ : evidence to support finding as a trait marker; þ /: some evidence in support of finding as a trait marker.

irrespective of mood state132 or lithium treatment,133 although reduced frontal choline in a sample of unmedicated bipolar patients in varying mood states has also been reported.153 There has been little consistency in the results of studies to date examining other neurochemicals with proton MRS. Interestingly, in a recent study of 21 stable remitted patients with BD taking lithium, patients were found to have increased hippocampal glutamate, which correlated strongly with NAA concentrations.134 There was also a negative correlation between hippocampal glutamate and diurnal cortisol, and the authors suggest that the high glutamate levels may be related to chronic lithium maintenance, which acts to protect the hippocampus from adverse effects of stress and glucocorticoids.134 Phosphorus MRS Increased levels of phosphomonoesters (PMEs) imply an increased rate of membrane phospholipid turnMolecular Psychiatry

over, whereas decreased PME levels indicate a stalling of membrane synthesis. Interestingly, PME appears to be increased in both the depressed and manic phases of BD,135 but reduced in frontal and temporal regions during the euthymic phase compared with healthy controls.137,138,154 Lower PME levels in euthymia are supported by a meta-analysis of phosphorus MRS findings in BD,155 supporting PME elevation as a state-related abnormality linked to mood episode and PME reduction as a traitrelated abnormality reflecting membrane synthesis inhibition. In summary, there are many inconsistencies in the MRS data to date, but most evidence supports a traitrelated reduction of NAA and PME, especially in prefrontal or hippocampal subregions, and increased choline in the basal ganglia. These neurochemical abnormalities are likely to reflect neuronal loss and membrane abnormalities underlying the disorder in these regions and may be normalized by moodstabilizing treatments.


Functional neuroimaging PET studies PET has been used to study regional brain activity by the measurement of glucose metabolism and regional cerebral blood flow at rest or during completion of cognitive tasks. State-related alterations in prefrontal activation during mood exacerbation is shown by significantly reduced blood flow and glucose metabolism in the subgenual prefrontal cortex in unmedicated bipolar patients in the depressed phase compared with healthy controls,90 whereas patients in the manic phase have increased blood flow in the left dorsal anterior cingulate cortex and left head of caudate when compared with euthymic patients.156 Other evidences showed that manic patients display reduced activity in right-sided prefrontal cortex during cognitive testing and reduced activity bilaterally in the orbitofrontal cortex at rest, when compared with either euthymic patients or healthy controls.157 These findings suggest reduced control of prefrontal executive function in the manic state, which concurs with the clinical presentation of such patients. Impaired learning of new verbal information has been associated with failure to activate the left dorsolateral prefrontal cortex in euthymic bipolar patients, suggesting that trait-related impaired dorsolateral prefrontal cortex functioning may underlie the well-recognized memory deficits that persist into euthymia.158 Reduced orbitofrontal cortex and increased dorsal anterior cingulate activity were shown both in euthymic patients and in their unaffected siblings during a task designed to introduce transient sadness, indicating a trait abnormality in this network.139 Bipolar patients also had reduced activity in the medial frontal cortex, whereas their siblings had increased activity in this area, suggesting a potential protective/resilience effect in siblings.139 The same authors had reported earlier that euthymic patients display reduced activity in the dorsal anterior cingulate on emotional challenge.140 SPECT studies A small SPECT study of regional cerebral perfusion in euthymic BD identified reduced blood flow in distributed regions, with the greatest hypoperfusion present in the cingulate region.159 SPECT has also been applied to the investigation of receptor function in BD, with one study finding no evidence of altered striatal dopamine binding in response to amphetamine challenge in a sample of euthymic BD patients compared with healthy controls.160 fMRI studies fMRI has been used to assess relative changes in regional cerebral blood flow in response to cognitive or affective tasks in BD patients in various clinical phases. Depressed bipolar patients tend to have

decreased prefrontal activation and manic patients tend to have decreased prefrontal activation and increased anterior cingulate activation. Other anterior limbic areas also display increased activation, including the striatum, thalamus and amygdala during manic or depressive state. These findings are consistent with a model in which impaired prefrontal (cognitive) modulation of anterior limbic (emotional) networks underlies mood exacerbation in BD.141,161 Several fMRI studies of confirmed euthymic samples of patients with BD have been published in recent years, which have investigated regional haemodynamic activity during the stimulation of cognitive and/or affective neural networks.

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Cognitive tasks Examination of cerebral activity in response to a colour-naming Stroop task in patients during different phases of bipolar illness revealed state-related prefrontal activation, in addition to left rostral ventral prefrontal cortex region attenuation in all patient groups, including euthymic patients, compared with controls, which indicates an enduring trait vulnerability.142 While performing a counting Stroop interference task, euthymic bipolar patients displayed reduced activation of the ventrolateral prefrontal region, temporal regions, midline cerebellum and putamen, suggesting failure to activate secondary brain regions involved in the prevention of impulsive responses.143 Strakowski et al.161 also identified increased activation of anterior limbic regions and corresponding abnormal activation of the visual association cortex during an attentional task in unmedicated euthymic bipolar patients compared with controls, despite similar performance on the task. Adler et al.144 performed a two-back working memory task with euthymic bipolar patients and matched controls. After controlling for poorer performance among patients, bipolar subjects still showed greater activation of the fronto-polar prefrontal cortex, temporal cortex, posterior parietal cortex and thalamus, suggesting activation of alternative neural networks in patients to complete this working memory task. Using a similar working memory task in a sample of lithiumtreated euthymic bipolar 1 patients, Monks et al.162 reported increased activation in right medial frontal, left precentral and left supramarginal regions and reduced activation in bilateral frontal, temporal and parietal regions compared with controls, interpreted as failure to engage fronto-temporal executive function as a core trait of BD. An fMRI study of a language processing task in a similar sample reported increased activity in euthymic patients within frontal and cerebellar/fusiform/lingual regions, areas known to have a role in executive function and language generation.163 An event-related working memory experiment of euthymic bipolar patients identified attenuated prefrontal activity across three conditions of working memory load, further supporting dysfunctional fronto-cortico-limbic networks during execuMolecular Psychiatry


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tive processing as a trait feature of BD.150 A recent working memory fMRI study of remitted patients with BD from multiply affected families and their unaffected first-degree relatives showed that unaffected relatives displayed increased activity in the left ventrolateral prefrontal region while performing the task compared with controls, supportive of increased activity in this region as a potential endophenotypic trait for BD.145 Affective tasks Studies incorporating affect-recognition tasks involve the presentation of verbal or visual material designed to stimulate emotions such as fear, sadness and happiness in subjects to explore the neural substrate of emotional dysregulation. A mixture of depressed and euthymic bipolar patients displayed increased subcortical and ventral prefrontal cortical responses to positive and negative facial emotional expressions, when compared with controls or unipolar depressed patients.148 This response was largely uncorrelated with depression severity, and the authors interpreted their findings as supporting an increased responsiveness within neural systems important for emotion processing as characterizing BD. Application of an emotional Stroop word task designed to implicitly induce affect identified diminished activation in subcortical and cortical regions, including the left ventral prefrontal cortex, in a sample of 12 euthymic patients compared with controls,164 interpreted by the authors as indicative of a constrained ability of such patients to engage affective processing. A further fMRI study of an explicit facial emotional regulation task involving fear, disgust and neutral emotions identified hyperactivity in the hippocampus, inferior parietal and superior temporal cortices and the cerebellum among 10 female euthymic patients compared with matched controls, whereas patients had less activation in response to the disgust task including that in prefrontal regions.165 An fMRI investigation of a word-based memory task designed to evoke affect in 10 euthymic bipolar patients compared with matched controls revealed a reduced activation in response to both positive and negative affect in several brain regions, including prefrontal, limbic, subcortical and cingulate areas, in the bipolar group.166 Wessa et al.149 used fMRI to examine the emotional modulation of cognitive processes in 17 euthymic patients and matched controls using emotional and non-emotional go/no-go tasks. Emotion-specific neural differences were detected as patients displayed overactivation in ventral–limbic, temporal and dorsal anterior and posterior cingulate regions during emotional go/no-go conditions, whereas no differences were observed when all go/no-go conditions were compared with the resting state. The authors interpreted their results as reflecting possible trait-related altered emotional modulation of cognitive processing in BD.


In summary, there has been an upsurge of functional neuroimaging studies of euthymic BD, assessing the resting state and a range of cognitive and affective paradigms. Despite the wide variety of tasks utilized, there is repeated evidence from these studies of abnormalities within key neural networks implicated in emotional regulation, including anterior limbic regions, ventral and dorsal prefrontal regions. The studies generally include small numbers of participants and varying research methodologies and so the variable regional activations are unsurprising. However, several studies do identify increased activation in the emotional regulation brain areas incorporating subcortical, anterior limbic and temporal regions, in particular in response to tasks that involve emotional stimulation. On the other hand, studies mostly support attenuated cerebral activity in the more cognitive brain regions, including the dorsolateral prefrontal cortex and dorsal anterior cingulate. This research supports the existence of trait-based neural system abnormalities and is broadly consistent with a model by which there is inherently impaired cognitive control in association with increased responsiveness of brain regions involved in emotional regulation (Figure 2). This pattern of neural network abnormality then becomes accentuated during episodes of mood exacerbation. These studies press the case for further research to more clearly elucidate abnormalities in these neural networks, including replication in larger samples, examination of medication effects and longitudinal studies through different phases of illness.167

Conclusion and recommendations This review has drawn together several strands of research in BD to highlight fundamental neurobiological trait abnormalities that may underpin this illness. Table 1 summarizes the trait abnormalities detectable at several levels of scale from intracellular molecular processes through to neural brain networks. These include elevated PKA activity, altered intracellular calcium signalling, enhanced pro-inflammatory cytokine production, glucocorticoid receptor dysfunction, reduced prefrontal NAA, white matter abnormalities and impaired functioning of anterior limbic and prefrontal neural networks. There is insufficient evidence to integrate these diverse findings across various levels of scale into a definitive model of pathophysiology in BD; however, the findings do converge on trait neurobiological abnormalities within linked systems and neuroanatomical regions, which enables some inevitably speculative syntheses of the findings. For example, glucocorticoid excess and resistance, inflammatory activation and abnormal neurotrophic functioning could be linked to dendritic atrophy, reduced neuronal membrane synthesis, impaired neurogenesis and gliogenesis with subsequent volumetric deficits detectable on MR imaging.


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DLPFC: Dorsolateral prefrontal cortex VLPFC: Ventrolateral prefrontal cortex DMPFC: Dorsomedial prefrontal cortex ACG: Anterior cingulate gyrus

Proposed reduced responsiveness in areas of brain associated with cognitive control

Dorsal ACG

DMPFC

Ventral ACG

Proposed increased responsiveness in areas of brain involved in emotional regulation

Amygdala

Figure 2 Proposed areas of over- and under-responsiveness in euthymic bipolar disorder. Current findings from neuroimaging studies are suggestive of abnormalities in the key neural networks that are responsible for emotional regulation, in particular the anterior limbic and ventral/dorsal prefrontal regions as highlighted above. Studies of euthymic patients suggest that there is impaired cognitive control in association with increased responsiveness associated with brain regions involved in emotional regulation. Modified and reproduced with permission from Molecular Psychiatry (2008) 13: 833–857. doi:10.1038/mp.2008.65.

The hippocampus is particularly plastic and susceptible to the atrophic or neurotoxic effects of glucocorticoid excess, but such effects may be reversed by the neurotrophic effects of lithium, or of other mood stabilizers, on the medial temporal lobe. White matter abnormalities may disrupt key tracts and fuel the disturbed activation of neural networks underlying normal mood function. For example, if the long association fibres connecting key prefrontal and anterior limbic system networks were disrupted by white matter abnormalities, the removal of this prefrontal or cognitive inhibitory control could unleash increased cerebral activity within anterior limbic networks and the propensity to develop an abnormal mood state. Despite the fact that inherent abnormalities appear to exist at many levels in BD, there are still considerable inconsistencies in the literature and it frequently remains unclear as to whether these abnormalities are causes or consequences of the illness or its treatment. Studies to date have tended to include relatively small numbers of patients and even euthymic/remitted samples can have substantial sources of clinical heterogeneity. These include the presence of subclinical manic or depressive symptoms, mixtures of diagnostic subtypes (bipolar I disorder, bipolar II disorder, rapid cycling

illness, presence of psychotic symptoms), co-morbid substance or alcohol misuse and family history. Furthermore, many patients with euthymic BD continue to experience impaired occupational and social functioning.168 One of the major limitations of the euthymic strategy is the extent of uncertainty to which changes are pharmacologically induced rather than trait based. Animal studies suggest that lithium and sodium valproate stimulate the extracellular signal-regulated kinase pathway, which may result in their anti-manic effect.151 In addition, animal studies have shown that these two agents are associated with increased levels of neuroprotective proteins in the frontal cortex,169 inhibition of apoptotic enzymes146 and downregulation of synaptic expression of glutamate receptors in the hippocampus,147 indicating a neuroprotective and neurotrophic role for these mood stabilizers in BD.105 Neuroimaging studies reviewed above suggest a neurotrophic effect for lithium, and possibly also for valproate and quetiapine in BD.104–109,111,112,152 The vast majority of the literature to date has been cross-sectional in nature. There is an inherent weakness in such studies as mood state, medication usage and disease progression most likely have dynamic and possibly interacting effects on many of the Molecular Psychiatry


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neurobiological indices reviewed in this paper. It is often impossible with such studies to determine whether neurobiological abnormalities, such as those of cellular functioning or neural network activation, are primary sources of pathophysiology or are compensatory mechanisms. Longitudinal studies bring the major advantage of powerful within-subject design and the possibility of teasing apart such dynamic and interacting effects. Given the subtle alterations of neurobiological measures in BD, further cross-sectional studies of small heterogeneous samples are likely to provide only incremental advances in knowledge rather than secure any breakthroughs in the understanding of the aetiopathogenesis of BD. Future clinical investigations of these traits, which are likely to be most informative, will incorporate one or more of the following study designs: (i) purification of clinically homogenous patient subgroups, (ii) the assessment of medication-free patients, (iii) assessment of firstepisode manic patients, (iv) assessment of unaffected first-degree relatives or co-twins of patients, (v) assessment of the relationship between genotypic variation in putative susceptibility genes for BD and trait abnormalities, (vi) interinstitutional collaborative ventures to acquire complementary data on large numbers of patients and (vii) longitudinal studies across different phases of illness. Although methodologically challenging, in particular for multivariate data such as imaging, such longitudinal studies are feasible and some have been completed, for example assessing the effects of mood stabilizers on brain structure and the phosphoinositide system. We suggest that longitudinal studies should not sacrifice homogeneity for participant numbers but instead clinically homogenous cohorts of patients in a particular phase of illness, such as first-episode mania, euthymia and acute manic episode, should be reassessed during subsequent phases of illness through collaborative clinical research programmes. Technological advances in recent years have enabled a range of investigative tools to be applied to samples of patients with BD, many of which are highlighted in this review. Combining these tools with rigorous clinical research methodology will help clarify the trait abnormalities underlying BD and dissect them from those that reflect mood state. The successful application of this approach will assist in a better understanding of the pathophysiology of the illness and facilitate the identification of those neurobiological abnormalities that represent intermediate phenotypes for genetic studies of BD and those that represent biological markers for examining the impact of treatment approaches.

Conflict of interest The authors declare no conflict of interest. Funding sources: None. Molecular Psychiatry

References 1 Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 2006; 60: 93–105. 2 Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord 2004; 6: 171–182. 3 Ferrier IN, Stanton BR, Kelly TP, Scott J. Neuropsychological function in euthymic patients with bipolar disorder. Br J Psychiatry 1999; 175: 246–251. 4 Quraishi S, Frangou S. Neuropsychology of bipolar disorder: a review. J Affect Disord 2002; 72: 209–226. 5 Robinson LJ, Ferrier IN. Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord 2006; 8: 103–116. 6 Turnbull AV, Rivier C. Regulation of the HPA Axis by cytokines. Brain Behav Immun 1995; 9: 253–275. 7 Besedovsky HO, Del Rey A. Immune–neuroendocrine interactions: facts and hypotheses. Endocr Rev 1996; 17: 64–102. 8 Turnbull AV, Rivier CL. Regulation of the hypothalamic– pituitary–adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999; 79: 1–71. 9 Kiecolt-Glaser JK, Glaser R. Depression and immune function: central pathways to morbidity and mortality. J Psychosom Res 2002; 53: 873–876. 10 Papanicolaou DA, Yanovski JA, Cutler GBJ, Chrousos GP, Nieman LK. The pathophysiology roles of interleukin 6 in human disease. Ann Int Med 1998; 128: 127–134. 11 Maes M. Major depression and activation of the inflammatory response system. Adv Exp Med Biol 1999; 461: 25–46. 12 Song C, Dinan TG, Leonard BE. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord 1994; 30: 283–288. 13 Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R et al. Illness, cytokines and depression. Ann N Y Acad Sci 2000; 917: 478–487. 14 Fitzgerald P, O’Brien SM, Scully P, Rijkers K, Scott LV, Dinan TG. Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression. Psychol Med 2006; 36: 37–43. 15 Breunis MN, Kupka RW, Nolen WA, Suppes T, Denicoff KD, Leverich GS et al. High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder. Biol Psychiatry 2003; 53: 157–165. 16 Liu H-C, Yang Y-Y, Chou Y-M, Chen K-P, Shen WW, Leu S-J. Immunologic variables in acute mania of bipolar disorder. J Neuroimmunol 2004; 150: 116–122. 17 O’Brien SM, Scully P, Scott LV, Dinan TG. Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord 2006; 90: 263–267. 18 Kim Y-K, Jung H-G, Myint A-M, Kim H, Park S-H. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord 2007; 104: 91–95. 19 Boufidou F, Nikolaou C, Alevizos B, Liappas IA, Christodoulou GN. Cytokine production in bipolar affective disorder patients under lithium treatment. J Affect Disord 2004; 82: 309–313. 20 Maes M, Delange J, Ranjan R, Meltzer HY, Desnyder R, Cooremans W et al. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res 1997; 66: 1–11. 21 Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res 1995; 29: 141–152. 22 Gibbons JL, McHugh PR. Plasma cortisol in depressive illness. J Psychiatr Res 1962; 1: 162–171. 23 Carroll BJ. Use of the dexamethasone test in depression. J Clin Psychiatry 1982; 43: 44–50. 24 Holsboer F, von Bardeleben U, Wiedemann K, Muller OA, Stalla GK. Serial assessment of corticotropin-releasing hormone response after dexamethasone in depression. Implications for


25

26 27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

pathophysiology of DST non-suppression. Biol Psychiatry 1987; 22: 228–234. Heuser I, Yassouridis A, Holsboer F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res 1994; 28: 341–356. Pariante CM. The glucocorticoid receptor: part of the solution or part of the problem? J Psychopharmacol 2006; 20(Suppl): 79–84. Holsboer F, Lauer CJ, Schreiber W, Krieg JC. Altered hypothalamic–pituitary–adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 1995; 62: 340–347. Schmider J, Lammers C-H, Gotthardt U, Dettling M, Holsboer F, Heuser I. Combined Dexamethasone/Corticotropin-Releasing Hormone Test in acute and remitted manic patients, in acute depression and in normal controls:I. Biol Psychiatry 1995; 38: 797–802. Rybakowski JK, Twardowska K. The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness. J Psychiatr Res 1999; 33: 363–370. Watson S, Gallagher P, Ritchie JC, Ferrier N, Young AH. Hypothalamic–pituitary–adrenal axis function in patients with bipolar disorder. Br J Psychiatry 2004; 184: 496–502. Watson S, Thompson JM, Ritchie JC, Ferrier IN, Young AH. Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function. Bipolar Disord 2006; 8: 85–90. Knijff EM, Breunis MN, van Geest MC, Kupka RW, Ruwhof C, de Wit HJ et al. A relative resistance of T cells to dexamethasone in bipolar disorder. Bipolar Disord 2006; 8: 740–750. Bauer ME, Papadopoulos A, Poon L, Perks P, Lightman SL, Vheckley S et al. Altered glucocorticoid immunoregulation in treatment resistant depression. Psychoneuroendocrinology 2003; 28: 49–65. Ryan MCM, Sharifi N, Condren R, Thakore JH. Evidence of basal pituitary–adrenal overactivity in first-episode, drug naive patients with schizophrenia. Psychoneuroendocrinology 2004; 29: 1065–1070. Gallagher P, Watson S, Smith MS, Young AH, Ferrier IN. Plasma cortisol–dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder. Schizophr Res 2007; 90: 258–265. Young LT, Bakish D, Beaulieu S. The neurobiology of treatment response to antidepressants and mood stabilising medications. J Psychiatry Neurosci 2002; 27: 260–265. Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T et al. Brain derived neurotrophic factor changes in serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1256–1260. Gonul AS, Akdeniz F, Taneli F, Donat O, Eker C, Vahip S. Effect of treatment on serum brain derived neurotrophic factor levels in depressed patients. Eur Arch Clin Neurosci 2005; 255: 381–386. Quiroz JA, Singh J, Gould TD, Denicoff KD, Zarate Jr CA, Manji HK. Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology. Mol Psychiatry 2004; 9: 756–776. Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R, Perez J. Protein kinase activity in platelets from patients with bipolar disorder. J Affect Disord 2003; 76: 249–253. Perez J, Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R. Abnormalities of cyclic adenosine monophosphate signalling in platelets from untreated patients with bipolar disorder. Arch Gen Psychiatry 1999; 56: 248–253. Karege F, Schwald M, Papadimitriou P, Lachausse C, Cisse M. The cAMP-dependent protein kinase A and brain-derived neurotrophic factor expression in lymphoblast cells of bipolar affective disorder. J Affect Disord 2004a; 79: 187–192. Karege F, Schwald M, Kouaissi RE. Drug-induced decrease of protein kinase A activity reveals alteration in BDNF expression of bipolar affective disorder. Neuropsychopharmacology 2004b; 29: 805–812. Monteleone P, Serritella C, Martiadis V, Maj M. Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disord 2008; 10: 95–100.

45 Cunha ABM, Frey BN, Andreazza AC, Goi JD, Rosa AR, Goncalves CA et al. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett 2006; 398: 215–219. 46 Machado-Viera R, Dietrich MO, Leke R, Cereser VH, Zanatto V, Kapczinski F et al. Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biol Psychiatry 2007; 61: 142–144. 47 Gama CS, Andreazza AC, Kunz M, Berk M, Belmonte-de-Abreu PS, Kapczinski F. Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder. Neurosci Lett 2007; 420: 45–48. 48 Palomino A, Vallejo-Illarramendi A. Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients. Schizophr Res 2006; 86: 321–322. 49 Young LT, Li PP, Kamble A, Siu KP, Warsh JJ. Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder. Am J Psychiatry 1994; 151: 594–596. 50 Manji HK, Chen G, Shimon H, Hsiao JK, Potter WZ, Belmaker RH. Guanine nucleotide-binding proteins in bipolar affective disorder. Effects of long-term lithium treatment. Arch Gen Psychiatry 1995; 52: 135–144. 51 Mitchell PB, Manji HK, Chen G, Jolkovsky L, Smith-Jackson E, Denicott K et al. High levels of Gsa in platelets of euthymic patients with bipolar affective disorder. Am J Psychiatry 1997; 154: 218–223. 52 Avissar S, Nechamkin Y, Barki-Harrington L, Roitman G, Schreiber G. Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent. J Affect Disord 1997; 43: 85–93. 53 Schreiber G, Avissar S, Danon A, Belmaker RH. Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry 1991; 29: 273–280. 54 Alda M, Keller D, Grof E, Turecki G, Cavazzoni P, Duffy A et al. Is lithium response related to Gsa levels in transformed lymphoblasts from subjects with bipolar disorder? J Affect Disord 2001; 65: 117–122. 55 Hahn CG, Umapathy C, Wang HY, Koneru R, Levinson DF, Friedman E. Lithium and valproic acid treatments reduce PKC activation and receptor–G protein coupling in platelets of bipolar manic patients. J Psychiatr Res 2005; 39: 355–363. 56 Bezchlibnyk Y, Young LT. The neurobiology of bipolar disorder: focus on signal transduction pathways and the regulation of gene expression. Can J Psychiatry 2002; 47: 135–148. 57 Brown AS, Mallinger AG, Renbaum LC. Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate in bipolar mania. Am J Psychiatry 1993; 150: 1252–1254. 58 Soares JC, Dippold CS, Wells KF, Frank E, Kupfer DJ, Mallinger AG. Increased platelet membrane phosphatidylinositol-4,5-bisphosphate in drug-free depressed bipolar patients. Neurosci Lett 2001; 299: 150–152. 59 Wang H-Y, Markowitz P, Levinson D, Undie AS, Friedman E. Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J Psychiatr Res 1999; 33: 171–179. 60 Soares JC, Mallinger AG, Dippold CS, Frank E, Kupfer DJ. Platelet membrane phospholipids in euthymic bipolar disorder patients: are they affected by lithium treatment? Biol Psychiatry 1999; 45: 453–457. 61 Soares JC, Mallinger AG, Dippold CS, Forster Wells K, Frank E, Kupfer DJ. Effects of lithium on platelet membrane phosphoinositides in bipolar disorder patients: a pilot study. Psychopharmacology 2000; 149: 12–16. 62 Berridge MJ, Downes CP, Hanley MR. Lithium amplifies agonistdependent phosphatidylinositol responses in brain and salivary glands. Biochem J 1982; 206: 587–595. 63 Manji HK, Potter WZ, Lenox RH. Signal transduction pathways: molecular targets for lithium’s actions. Arch Gen Psychiatry 1995; 52: 531–543. 64 Manji HK, Lenox RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry 2000; 48: 518–530. 65 Emamghoreishi M, Schlichter L, Li PP, Parikh S, Sen J, Kamble A et al. High intracellular calcium concentrations in

843



844 66

67

68

69

70

71

72

73

74 75

76

77 78

79

80

81

82

83

84

85

transformed lymphoblasts from subjects with bipolar I disorder. Am J Psychiatry 1997; 154: 976–982. Emamghoreishi M, Li PP, Schlichter L, Parikh S, Cooke R, Warsh JJ. Associated disturbances in calcium homeostasis and G protein-mediated cAMP signalling in bipolar I disorder. Biol Psychiatry 2000; 48: 665–673. Perova T, Wasserman MJ, Li PP, Warsh JJ. Hyperactive intracellular calcium dynamics in B lymphoblasts from patients with bipolar I disorder. Int J Neuropsychopharmacol 2008; 11: 185–196. El Khoury A, Petterson U, Kallner G, Aberg-Wistedt A, StainMalmgren R. Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1063–1069. Dubovsky SL, Thomas M, Hijazi A, Murphy J. Intracellular calcium signalling in peripheral cells of patients with bipolar affective disorder. Eur Arch Psychiatry Clin Neurosci 1994; 243: 229–234. Hahn C-G, Gomez G, Restrepo D, Friedman E, Josiassen R, Pribitkin EA et al. Aberrant intracellular calcium signalling in olfactory neurons from patients with bipolar disorder. Am J Psychiatry 2005; 162: 616–618. Kato T, Ishiwata M, Mori K, Washizuka S, Tajima O, Akiyama T et al. Mechanisms of altered Ca2 þ signalling in transformed lymphoblastoid cells from patients with bipolar disorder. Int J Neuropsychopharmacol 2003; 6: 379–389. Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 2004; 61: 300–308. Elkis H, Friedman L, Wise A, Meltzer HY. Meta-analysis of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Arch Gen Psychiatry 1995; 52: 735–746. Pearlson GD, Veroff AE. Computerised tomographic scan changes in manic-depressive illness. Lancet 1981; 2: 470. McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham PC, Kalidindi S et al. Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004; 56: 411–417. Kempton MJ, Geddes JR, Ettinger U, Williams SCR, Grasby PM. Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry 2008; 65: 1017–1032. Hoge EA, Friedman L, Schulz SC. Meta-analysis of brain size in bipolar disorder. Schizophr Res 1999; 37: 177–181. McDonald C, Marshall N, Sham PC, Bullmore ET, Schulze K, Chapple B et al. Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives. Am J Psychiatry 2006; 163: 478–487. Strakowski SM, DelBello MP, Zimmerman ME, Getz GE, Mills NP, Ret J et al. Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. Am J Psychiatry 2002; 159: 1841–1847. Strasser HC, Lilyestrom J, Ashby ER, Honeycutt NA, Schretlen DJ, Pulver AE et al. Hippocampal and ventricular volumes in psychotic and non-psychotic bipolar patients compared with schizophrenia patients and community control subjects: a pilot study. Biol Psychiatry 2005; 57: 633–639. Hauser P, Matochik J, Altshuler LL, Denicoff KD, Conrad A, Li X et al. MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders. J Affect Disord 2000; 60: 25–32. Altshuler LL, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K et al. An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry 2000; 48: 147–162. Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J. Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry 1998; 55: 663–664. Brambilla P, Harenski K, Nicoletti M, Sassi RB, Mallinger AG, Frank E et al. MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res 2003; 37: 287–295. Strakowski SM, Del Bello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM et al. Brain magnetic resonance imaging of


86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

structural abnormalities in bipolar disorder. Arch Gen Psychiatry 1999; 56: 254–260. Pearlson GD, Barta PE, Powers RE, Menon RR, Richards SS, Aylward EH et al. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol Psychiatry 1997; 41: 1–4. Blumberg HP, Kaufman J, Martin A, Whiteman R, Zhang JH, Gore JC et al. Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003; 60: 1201–1208. Rosso IM, Killgore WD, Cintron CM, Gruber SA, Tohen M, Yurgelun-Todd DA. Reduced amygdala volumes in first episode bipolar disorder and correlation with cerebral white matter. Biol Psychiatry 2007; 61: 743–749. Lopez-Larson MP, Del Bello MP, Zimmerman ME, Schwiers ML, Strakowski SM. Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry 2002; 52: 93–100. Drevets WC, Price JL, Simpson JRJ, Todd RD, Reich T, Vannier M et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386: 824–827. Sharma V, Menon RR, Carr TJ, Densmore M, Mazmanian D, Williamson PC. An MRI study of subgenual prefrontal cortex in patients with familial and non-familial bipolar I disorder. J Affect Disord 2003; 77: 167–171. Zimmerman ME, Del Bello MP, Getz GE, Shear PK, Strakowski SM. Anterior cingulate subregion volumes and executive function in bipolar disorder. Bipolar Disord 2006; 8: 281–288. Brambilla P, Nicoletti MA, Harenski K, Sassi RB, Mallinger AG, Frank E et al. Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects. Neuropsychopharmacology 2002; 27: 792–799. McIntosh AM, Job DE, Moorhead TW, Harrison LK, Forrester K, Lawrie SM et al. Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives. Biol Psychiatry 2004; 56: 544–552. Nugent AC, Milham MP, Bain EE, Mah L, Cannon DM, Marrett S et al. Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry. Neuroimage 2006; 30: 485–497. Lyoo IK, Sung YH, Dager SR, Friedman SD, Lee J-Y, Kim SJ et al. Regional cerebral cortical thinning in bipolar disorder. Bipolar disord 2006; 8: 65–74. Chen X, Wen W, Malhi GS, Ivanovski B, Sachdev PS. Regional gray matter changes in bipolar disorder: a voxel-based morphometric study. Aust N Z J Psychiatry 2007; 41: 327–336. Adler CM, Levine AD, Del Bello MP, Strakowski SM. Changes in gray matter volume in patients with bipolar disorder. Biol Psychiatry 2005; 58: 151–157. Lochhead RA, Parsey RV, Oquendo MA, Mann JJ. Regional brain gray matter volume differences in patients with bipolar disorder as assessed by optimised voxel-based morphometry. Biol Psychiatry 2004; 55: 1154–1162. Adler CM, DelBello MP, Jarvis K, Levine A, Adams J, Strakowski SM. Voxel-based study of structural changes in first-episode patients with bipolar disorder. Biol Psychiatry 2007; 61: 776–781. Bearden CE, Thompson PM, Dalwani M, Hayashi KM, Lee AD, Nicoletti M et al. Greater cortical gray matter density in lithiumtreated patients with bipolar disorder. Biol Psychiatry 2007; 62: 7–16. Bruno SD, Barker GJ, Cercignani M, Symms M, Ron MA. A study of bipolar disorder using magnetization transfer imaging and voxel-based morphometry. Brain 2004; 127: 2433–2440. McDonald C, Bullmore ET, Sham PC, Chitnis X, Suckling J, MacCabe J et al. Regional volume deviations of brain structure in schizophrenia and psychotic bipolar disorder: computational morphometry study. Br J Psychiatry 2005; 186: 369–377. Chuang DM, Manji HK. In search of the Holy Grail for the treatment of neurodegenerative disorders: has a simple cation been overlooked? Biol Psychiatry 2007; 62: 4–6. Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry 2000; 48: 740–754.

Neurobiological trait abnormalities in BD C Langan and C McDonald 106 Bearden CE, Thompson PM, Dutton RA, Frey BN, Peluso MAM, Nicoletti MA et al. Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder. Neuropsychopharmacology 2007; 33: 1229–1238. 107 Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK. Lithiuminduced increase in human brain grey matter. Lancet 2000; 356: 1241–1242. 108 Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT et al. Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology 2007; 195: 357–367. 109 Yucel K, Taylor VH, McKinnon MC, Macdonald K, Alda M, Young LT et al. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology 2008; 33: 361–367. 110 Foland LC, Altshuler LL, Sugar CA, Lee AD, Leow AD, Townsend J et al. Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. NeuroReport 2008; 19: 221–224. 111 Monkul ES, Matsuo K, Nicoletti MA, Dierschke N, Hatch JP, Dalwani M et al. Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study. Neurosci Lett 2007; 429: 7–11. 112 Atmaca M, Ozdemir H, Cetinkaya S, Parmaksiz S, Belli H, Poyraz AK et al. Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine. J Psychiatr Res 2007; 41: 821–827. 113 Altshuler LL, Curran JG, Hauser P, Mintz J, Denicoff K, Post R. T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry 1995; 152: 1139–1144. 114 Ahn KH, Lyoo IK, Lee HK, Song IC, Oh JS, Hwang J et al. White matter hyperintensities in subjects with bipolar disorder. Psychiatry Clin Neurosci 2004; 58: 516–521. 115 Pillai JJ, Friedman L, Stuve TA, Trinidad S, Jesberger JA, Lewin JS et al. Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder. Psychiatry Res 2002; 114: 51–56. 116 Beyer JL, Taylor WD, MacFall JR, Kuchibhatla M, Payne ME, Provenzale JM et al. Cortical white matter microstructural abnormalities in bipolar disorder. Neuropsychopharmacology 2005; 30: 2225–2229. 117 Adler CM, Holland SK, Schmithorst V, Wilke M, Weiss KL, Pan H et al. Abnormal frontal white matter tracts in bipolar disorder: a diffusion tensor imaging study. Bipolar Disord 2004; 6: 197–203. 118 Haznedar MM, Roversi F, Pallanti S, Baldini-Rossi N, Schnur DB, LiCalzi EM et al. Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses. Biol Psychiatry 2005; 57: 733–742. 119 Regenold WT, D’Agostino CA, Ramesh N, Hasnain M, Roys S, Gullapalli RP. Diffusion-weighted magnetic resonance imaging of white matter in bipolar disorder: a pilot study. Bipolar Disord 2006; 8: 188–195. 120 Adler CM, Adams J, DelBello MP, Holland SK, Schmithorst V, Levine A et al. Evidence of white matter pathology in bipolar disorder adolescents experiencing their first episode of mania: a diffusion tensor imaging study. Am J Psychiatry 2006; 163: 322–324. 121 Davis KA, Kwon A, Cardenas VA, Deicken RF. Decreased cortical gray and cerebral white matter in male patients with familial bipolar 1 disorder. J Affect Disord 2004; 82: 475–485. 122 El-Badri SM, Cousins DA, Parker S, Ashton HC, McAllister VL, Ferrier IN et al. Magnetic resonance imaging abnormalities in young euthymic patients with bipolar affective disorder. Br J Psychiatry 2006; 189: 81–82. 123 Houenou J, Wessa M, Douaud G, Leboyer M, Chanraud S, Perrin M et al. Increased white matter connectivity in euthymic bipolar disorder patients: diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex. Mol Psychiatry 2007; 12: 1001–1010.

124 Ahearn EP, Steffens DC, Cassidy F, Van Meter SA, Provenzale JM, Seldin MF et al. Familial leukoencephalopathy in bipolar disorder. Am J Psychiatry 1998; 155: 1605–1607. 125 Kieseppa T, Van Erp TG, Haukka J, Partonen T, Cannon TD, Poutanen VP et al. Reduced left hemispheric white matter volume in twins with bipolar 1 disorder. Biol Psychiatry 2003; 54: 896–905. 126 McDonald C, Bullmore ET, Sham PC, Chitnis X, Wickham H, Bramon E et al. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004; 61: 974–984. 127 Yildiz-Yesiloglu A, Ankerst DP. Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 969–995. 128 Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 2005; 10: 900–919. 129 Scherk H, Backens M, Schneider-Axmann T, Kemmer C, Usher J, Reith W et al. Neurochemical pathology in hippocampus in euthymic patients with bipolar 1 disorder. Acta Psychiatr Scand 2008; 117: 283–288. 130 Silverstone PH, Wu RH, O’Donnell T, Ulrich M, Asghar SJ, Hanstock CC. Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar disorder patients. Int Clin Psychopharmacol 2003; 18: 73–79. 131 Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB et al. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects. Biol Psychiatry 2000; 48: 1–8. 132 Hamakawa H, Kato T, Murashita J, Kato N. Quantitative proton magnetic resonance spectroscopy of the basal ganglia in patients with affective disorders. Eur Arch Clin Neurosci 1998; 248: 53–58. 133 Kato T, Hamakawa H, Shioiri T, Murashita J, Takahashi Y, Takahashi S et al. Choline-containing compounds detected by proton magnetic resonance spectroscopy in the basal ganglia in bipolar disorder. J Psychiatry Neurosci 1996; 21: 248–254. 134 Colla M, Schubert F, Bubner M, Heidenreich JO, Bajbouj M, Seifert F et al. Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol. Mol Psychiatry 2008. (e-pub ahead of print). doi: 10.1038/mp.2008.26. 135 Kato T, Takahashi S, Shioiri T, Murashita J, Hamakawa H, Inubushi T. Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 1994; 31: 125–133. 136 Atmaca M, Yildirim H, Ozdemir H, Ogur E, Tezcan E. Hippocampal 1H MRS in patients with bipolar disorder taking valproate versus valproate plus quetiapine. Psychol Med 2007; 37: 121–129. 137 Kato T, Takahashi S, Shioiri T, Inubushi T. Brain phosphorus metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 1992; 26: 223–230. 138 Deicken RF, Weiner MW, Fein G. Decreased temporal lobe phosphomonoesters in bipolar diosrder. J Affect Disord 1995; 33: 195–199. 139 Kruger S, Alda M, Young LT, Goldapple K, Parikh S, Mayberg HS. Risk and resilience markers in bipolar disorder: brain responses to emotional challenge in bipolar patients and their healthy siblings. Am J Psychiatry 2006; 163: 257–264. 140 Kruger S, Seminowicz D, Goldapple K, Kennedy SH, Mayberg HS. State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge. Biol Psychiatry 2003; 54: 1274–1283. 141 Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 2003; 54: 515–528.

845



846

142 Blumberg HP, Leung H-C, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC et al. A functional magnetic resonance imaging study of bipolar disorder. Arch Gen Psychiatry 2003; 60: 601–609. 143 Strakowski SM, Adler CM, Holland SK, Mills NP, DelBello MP, Eliassen JC. Abnormal fMRI brain activation in euthymic bipolar disorder patients during a counting Stroop interference task. Am J Psychiatry 2005; 162: 1697–1705. 144 Adler CM, Holland SK, Schmithorst V, Tuchfarber MJ, Strakowski SM. Changes in neuronal activation in patients with bipolar disorder during performance of a working memory task. Bipolar Disord 2004; 6: 540–549. 145 Drapier D, Surguladze S, Marshall N, Schulze K, Fern A, Hall MH et al. Genetic liability for bipolar disorder is characterised by excess frontal activation in response to a working memory task. Biol Psychiatry 2008; 64: 513–520. 146 Chen G, Huang LD, Jiang YM, Manji HK. The mood stabilizing agent valproate inhibits the activity of glycogen synthase kinase 3. J Neurochem 1999b; 72: 1327–1330. 147 Du J, Quiroz J, Peixiong Y, Zarate C, Manji HK. Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses. Neuron Glia Biol 2004; 1: 231–243. 148 Lawrence NS, Williams AM, Surguladze S, Giampietro V, Brammer MJ, Andrew C et al. Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biol Psychiatry 2004; 55: 578–587. 149 Wessa M, Houenou J, Paillere-Martinot M-L, Berthoz S, Artiges E, Leboyer M et al. Fronto-striatal overactivation in euthymic bipolar patients during an emotional go/nogo task. Am J Psychiatry 2007; 164: 638–646. 150 Lagopoulos J, Ivanovski B, Malhi GS. An event-related functional MRI study of working memory in euthymic bipolar disorder. J Psychiatry Neurosci 2007; 32: 174–184. 151 Einat H, Yuan P, Gould TD, Li J, Du JH, Zhang L et al. The role of the extracellular signal-regulated kinase signalling pathway in mood modulation. J Neurosci 2003; 23: 7311–7316. 152 Regenold WT. Lithium and increased cortical gray matter–more tissue or more water? Biol Psychiatry 2008; 63: e17. 153 Port JD, Unal SS, Mrazek DA, Marcus SM. Metabolic alterations in medication-free patients with bipolar disorder: a 3T CSFcorrected magnetic resonance spectroscopy imaging study. Psychiatry Res 2008; 162: 113–121. 154 Deicken RF, Fein G, Weiner MW. Abnormal frontal lobe phosphorus metabolism in bipolar disorder. Am J Psychiatry 1995; 152: 915–918. 155 Yildiz A, Sachs GS, Dorer DJ, Renshaw PF. 31P nuclear magnetic resonance spectroscopy findings in bipolar illness: a metaanalysis. Psychiatry Res 2001; 106: 181–191. 156 Blumberg HP, Stern E, Martinez D, Ricketts S, de Asis J, White T et al. Increased anterior cingulate and caudate activity in bipolar mania. Biol Psychiatry 2000; 48: 1045–1052.


157 Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, White T et al. Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder. Am J Psychiatry 1999; 156: 1986–1988. 158 Deckersbach T, Dougherty DD, Savage C, McMurrich S, Fischman AJ, Nierenberg A et al. Impaired recruitment of the dorsolateral prefrontal cortex and hippocampus during encoding in bipolar disorder. Biol Psychiatry 2006; 59: 138–146. 159 Culha AF, Osman O, Dogangun Y, Filiz K, Suna K, Kalkan ON et al. Changes in regional cerebral blood flow demonstrated by (99 m) Tc-HMPAO SPECT in euthymic patients. Eur Arch Psychiatry Clin Neurosci 2008; 258: 144–151. 160 Anand A, Verhoeff P, Seneca N, Zoghbi SS, Seibyl JP, Charney DS et al. Brain SPECT imaging of amphetamine-induced dopamine release in euthyymic bipolar disorder patients. Am J Psychiatry 2000; 157: 1108–1114. 161 Strakowski SM, Adler CM, Holland SK, Mills NP, DelBello MP. A preliminary fMRI study of sustained attention in euthymic, unmedicated bipolar disorder. Neuropsychopharmacology 2004; 29: 1734–1740. 162 Monks PJ, Thompson JM, Bullmore ET, Suckling J, Brammer MJ, Williams SC et al. A functional MRI study of working memory task in euthymic bipolar disorder: evidence for task-specific dysfunction. Bipolar Disord 2004; 6: 550–564. 163 Curtis VA, Thompson JM, Seal ML, Monks PJ, Lloyd AJ, Harrison L et al. The nature of abnormal language processing in euthymic bipolar I disorder: evidence for a relationship between task demand and prefrontal function. Bipolar Disord 2007; 9: 358–369. 164 Malhi GS, Lagopoulos J, Sachdev P, Ivanovski B, Shnier R. An emotional Stroop functional MRI study of euthymic bipolar disorder. Bipolar Disord 2005; 7(Suppl 5): 58–69. 165 Malhi GS, Lagopoulos J, Sachdev PS, Shnier R, Ketter T. Is a lack of disgust something to fear? A functional magnetic resonance imaging facial emotional recognition study in euthymic bipolar disorder patients. Bipolar Disord 2007; 9: 345–357. 166 Malhi GS, Lagopoulos J, Owen AM, Ivanovski B, Shnier R, Sachdev P. Reduced activation to implicit affect induction in euthymic bipolar patients: an fMRI study. J Affect Disord 2007; 97: 109–122. 167 Phillips ML, Ladouceur CD, Drevets WC. Neural systems underlying voluntary and automatic emotion regulation: toward a neural model of bipolar disorder. Mol Psychiatry 2008; 13: 829. 168 Gitlin MJ, Swendsen J, Heller TL, Hammen C. Relapse and impairment in bipolar disorder. Am J Psychiatry 1995; 152: 1635–1640. 169 Chen G, Zeng WZ, Jiang L, Yuan PX, Zhao J, Manji HK. The mood stabilizing agents lithium and valproate robustly increase the expression of the neuroprotective protein bcl-2 in the CNS. J Neurochem 1999; 72: 879–882.