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Background Bipolar disorder (BD) is a highly heritable psychiatric disorder characterized by episodes of manic and depressed mood states and associated with cortical brain abnormalities. Although the course of BD is often progressive, longitudinal brain imaging studies are scarce. It remains unknown whether brain abnormalities are static traits of BD or result from pathological changes over time. Moreover, the genetic effect on implicated brain regions remains unknown. Methods Patients with BD and healthy control (HC) subjects underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC subjects) and after 6 years (90 patients, 61 HC subjects). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between patients with BD and HC subjects across the whole brain. We related our findings to genetic risk for BD and tested for effects of demographic and clinical variables. Results Patients showed abnormal cortical thinning of temporal cortices and thickness increases in visual/somatosensory brain areas. Thickness increases were related to genetic risk and lithium use. Patients who experienced hypomanic or manic episodes between time points showed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between diagnostic BD subtypes I and II. Conclusions In the largest longitudinal BD study to date, we detected abnormal cortical changes with high anatomical resolution. We delineated regional effects of clinical symptoms, genetic factors, and medication that may explain progressive brain changes in BD. Our study yields important insights into disease mechanisms and suggests that neuroprogression plays a role in BD.

Background There is substantial inconsistency in results of brain structural magnetic resonance imaging studies in adult bipolar disorder. This is likely consequent upon limited statistical power of studies together with their clinical and methodological heterogeneity. The current study was undertaken to perform an international collaborative mega-analysis of regional volumetric measurements of individual patient and healthy subject data, to optimize statistical power, detect case-control differences, assess the association of psychotropic medication usage with brain structural variation, and detect other possible sources of heterogeneity. Methods Eleven international research groups contributed published and unpublished data on 321 individuals with bipolar disorder I and 442 healthy subjects. We used linear mixed effects regression models to evaluate differences in brain structure between patient groups. Results Individuals with bipolar disorder had increased right lateral ventricular, left temporal lobe, and right putamen volumes. Bipolar patients taking lithium displayed significantly increased hippocampal and amygdala volume compared with patients not treated with lithium and healthy comparison subjects. Cerebral volume reduction was significantly associated with illness duration in bipolar individuals. Conclusions The application of mega-analysis to bipolar disorder imaging identified lithium use and illness duration as substantial and consistent sources of heterogeneity, with lithium use associated with regionally specific increased brain volume.

Background At excitatory synapses, glutamate released from neurons is taken up by glial cells and converted to glutamine, which is cycled back to neurons. Alterations in this system are believed to play a role in the pathophysiology of bipolar disorder, but they have not been characterized in vivo. We examined the glutamine/glutamate ratio and levels of other metabolites in acute mania and schizophrenia in this exploratory study. Methods Data were obtained from 2 × 2 × 2 cm voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) using two-dimensional J -resolved proton magnetic resonance spectroscopy at 4 Tesla and analyzed using LCModel. Fifteen bipolar disorder patients with acute mania and 17 schizophrenia patients with acute psychosis were recruited from an inpatient unit; 21 matched healthy control subjects were also studied. Glutamine/glutamate ratio and N-acetylaspartate, creatine, choline, and myo-inositol levels were evaluated in a repeated measures design. Medication effects and relationship to demographic and clinical variables were analyzed. Results Glutamine/glutamate ratio was significantly higher in ACC and POC in bipolar disorder, but not schizophrenia, compared with healthy control subjects. N-acetylaspartate was significantly lower in the ACC in schizophrenia. Patients on and off lithium, anticonvulsants, or benzodiazepines had similar glutamine/glutamate ratios. Conclusions The elevated glutamine/glutamate ratio is consistent with glutamatergic overactivity and/or defective neuronal-glial coupling in acute mania, although medication effects cannot be ruled out. Abnormalities in glutamatergic neurotransmission and glial cell function in bipolar disorder may represent targets for novel therapeutic interventions.

Background Glycogen synthase kinase 3-beta (GSK3B) is a serine/threonine kinase which is directly inhibited by lithium. A −50T/C single nucleotide polymorphism (SNP) localized within the promoter region of the GSK3B gene has previously been shown to be associated with response to lithium prophylaxis in bipolar disorder. This study investigates the association of the GSK3B −50T/C SNP and response to lithium augmentation in acutely depressed antidepressant nonresponders. Methods Eighty-one patients who had not responded to at least one adequate trial of antidepressant monotherapy underwent a standardized trial of lithium augmentation for up to 8 weeks. We genotyped for the GSK3B −50T/C SNP using polymerase chain reaction and restriction fragment length polymorphism methods and investigated the association with remission. Results The allele frequencies in our sample were CC 14.8%, CT 48.2% and TT 37% (no deviation from the Hardy-Weinberg equilibrium). Carriers of the C-allele of the −50T/C SNP showed a significantly better response to lithium augmentation (hazard ratio: 2.70, p = .007), with a mean remission rate of 56.25% after 4 weeks compared to 31% in patients with the TT-genotype (χ 2 = 4.1; p = .04). Conclusions Our results support the finding of recent studies demonstrating a superior response of C-allele carriers with bipolar disorder to lithium prophylaxis.

Background The neurochemical effects of lithium in adolescents with bipolar disorder largely are unknown. This study used proton magnetic resonance spectroscopy ( 1 H MRS) to identify the in vivo effects of lithium on myo-inositol (mI) concentrations in adolescent bipolar depression. Methods Twenty-eight adolescents (12–18 years old) with bipolar I disorder, current episode depressed, received open-label lithium 30 mg/kg, adjusted to achieve serum levels of 1.0–1.2 mEq/L. The mI concentrations in the medial as well as the left and right lateral prefrontal cortices were measured at baseline, day 7, and day 42 of treatment. Changes in mI concentrations over time were analyzed. Results Significant main effects of time were observed for mI concentrations in the medial ( p = .03) and right lateral ( p = .05) prefrontal cortices. Baseline concentrations of mI were not significantly different from day 7 or day 42 concentrations. However, mI concentrations on day 42 were significantly higher than those on day 7 (p = .02) in both regions. Conclusions This study demonstrates that prefrontal mI concentrations do not significantly change from baseline after acute and chronic lithium treatment in adolescents with bipolar depression. Further investigation of the effect of lithium on mI is warranted to better understand possible mechanisms by which lithium exerts antidepressant activity.

Background Lithium and valproate (VPA) are used for treating bipolar disorder. The mechanism of mood stabilization has not been elucidated, but the role of inositol has gained substantial support. Lithium inhibition of inositol monophosphatase, an enzyme required for inositol recycling and de novo synthesis, suggested the hypothesis that lithium depletes brain inositol and attenuates phosphoinositide signaling. Valproate also depletes inositol in yeast, Dictyostelium, and rat neurons. This raised the possibility that the effect is the result of myo-inositol-1-phosphate (MIP) synthase inhibition. Methods Inositol was measured by gas chromatography. Human prefrontal cortex MIP synthase activity was assayed in crude homogenate. INO1 was assessed by Northern blotting. Growth cones morphology was evaluated in cultured rat neurons. Results We found a 20% in vivo reduction of inositol in mouse frontal cortex after acute VPA administration. As hypothesized, inositol reduction resulted from decreased MIP synthase activity: .21–.28 mmol/LVPA reduced the activity by 50%. Among psychotropic drugs, the effect is specific to VPA. Accordingly, only VPA upregulates the yeast INO1 gene coding for MIP synthase. The VPA derivative N-methyl-2,2,3,3,-tetramethyl-cyclopropane carboxamide reduces MIP synthase activity and has an affect similar to that of VPA on rat neurons, whereas another VPA derivative, valpromide, poorly affects the activity and has no affect on neurons. Conclusions The rate-limiting step of inositol biosynthesis, catalyzed by MIP synthase, is inhibited by VPA; inositol depletion is a first event shown to be common to lithium and VPA.

Background Functional and morphologic abnormalities of the cingulate cortex have been reported in mood disorder patients. To examine the involvement of anatomic abnormalities of the cingulate in bipolar disorder, we measured the volumes of this structure in untreated and lithium-treated bipolar patients and healthy control subjects, using magnetic resonance imaging (MRI). Methods The volumes of gray matter at the right and left anterior and posterior cingulate cortices were measured in 11 bipolar patients not taking any psychotropic medications (aged 38 ± 11 years, 5 women), 16 bipolar patients treated with lithium monotherapy (aged 33 ± 11 years, 7 women), and 39 healthy control subjects (aged 37 ± 10 years, 14 women). Volumetric measurements were made with T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5T, and were done blindly. Results Using analysis of covariance with age and intracranial volume as covariates, we found that untreated bipolar patients had decreased left anterior cingulate volumes compared with healthy control subjects [2.4 ± .3 cm 3 and 2.9 ± .6 cm 3 , respectively; F (1,58) = 6.4, p = .042] and compared with lithium-treated patients [3.3 ± .5 cm 3 ; F (1,58) = 11.7, p = .003]. The cingulate volumes in lithium-treated patients were not significantly different from those of healthy control subjects. Conclusions Our findings indicate that anatomic abnormalities in left anterior cingulate are present in bipolar patients. Furthermore, our results suggest that lithium treatment might influence cingulate volumes in bipolar patients, which could possibly reflect postulated neuroprotective effects of lithium.

Background Prior work reported elevated gray matter (GM) lactate and Glx (glutamate + glutamine + GABA) concentrations in unmedicated patients with bipolar disorder (BP) compared with healthy controls (HC). This study examined whether lithium (Li) and valproic acid (VPA) treatment modulated these chemicals. Methods A subset of previously reported BP patients were treated with Li ( n = 12, 3.6 ± 1.9 months) or VPA ( n = 9, 1.4 ± 1.7 months) and compared untreated HC subjects ( n = 12, 2.9 ± 2.4 months) using proton echo-planar spectroscopic imaging. Regression analyses (voxel gray/white composition by chemistry) were performed at each time point, and change scores computed. Metabolite relaxation and regions of interest (ROI) were also examined. Results Across treatment, Li-treated BP subjects demonstrated GM Glx decreases (Li–HC, p = .08; Li–VPA p = .04) and GM myo-inositol increases (Li–HC p = .07; Li–VPA p = .12). Other measures were not significant. Serum Li levels were positively correlated with Glx decreases at the trend level. Conclusions Li treatment of BP was associated with specific GM Glx decreases and myo-inositol increases. Findings are discussed in the context of cellular mechanisms postulated to underlie Li and VPA therapeutic efficacy.

Background The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants. Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder. The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression. Methods In a double-blind, placebo-controlled study, 21 patients with DSM-IV bipolar II disorder, depressive phase on therapeutic levels of lithium or valproate were randomly assigned to treatment with pramipexole ( n = 10) or placebo ( n = 11) for 6 weeks. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale. Results All subjects except for one in each group completed the study. The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect. A therapeutic response (>50% decrease in Montgomery-Asberg Depression Rating Scale from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo ( p = .02). One subject on pramipexole and two on placebo developed hypomanic symptoms. Conclusions The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression.

Background There have been repeated reports of antidepressant effects of thyroid hormones. In this study, we investigated whether antidepressant treatments enhance the concentrations of thyroid hormones in rat brain. Methods Each of the groups of rats was treated for 14 days with one of the following: an antidepressant drug (desipramine, paroxetine, venlafaxine, or tianeptine); a mood stabilizer (lithium or carbamazepine); or 8 hours' partial sleep deprivation. Thyroid hormone concentrations were quantified in homogenates, nuclei, mitochondria, synaptosomes, myelin, and microsomes in 11 rat brain areas. Results No drug effects were seen on nuclear triiodothyronine (T 3 ) concentrations in any brain area. In the amygdala, all antidepressant drugs enhanced the levels of T 3 in the myelin fraction. Triiodothyronine molecules were identified in the myelin by immunogold labeling. Quantification of the major lipid components showed a selective decrease in cholesterol in the myelin of the amygdala after desipramine treatment. Desipramine induced an increase in protein concentrations, 3,5-diiodothyronine levels, and the activity of the mitochondrial enzyme succinate dehydrogenase in the mitochondria of the amygdala. Lithium, carbamazepine, and partial sleep deprivation raised the levels of T 3 in synaptosomes of the amygdala. Conclusions These results demonstrate that thyroid hormones in the amygdala are a common target of different antidepressant and mood-stabilizing therapies.

Background There are similarities between schizophrenia and bipolar disorder, especially during the psychotic phase. Auditory gating deficits are common in both schizophrenia (does not remit postpsychotic event) and bipolar disorder (only during the manic phase). Lithium has been used to treat psychosis acutely in both bipolar disorder and schizophrenia. An animal model was used to assess the effects of lithium treatment on normal and deficient auditory gating. Methods Mice of the DBA/2 (deficient gating) and C3H (normal gating) strains were treated for 6 weeks with either standard rodent chow or rodent chow supplemented with 2.55g/kg lithium carbonate. After 6 weeks of treatment, auditory evoked potentials were recorded under anesthesia. Differences between the groups and treatments were determined using analysis of variance. Results The normally impaired DBA/2 mice showed improved auditory gating following lithium treatment, while the C3H mice, the benchmark “normal” mouse strain, were impaired after lithium treatment. Conclusions C3H mice treated with lithium had significantly impaired auditory gating as a result of treatment. This may be due to norepinephrine facilitation, through a blockade of presynaptic α2 autoreceptors. DBA/2 mice had improved gating as a result of treatment with lithium, likely due to improved functioning of the gamma-aminobutyric acid system.

Background: We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups. Methods: The TPO-Abs of outpatients with DSM-IV bipolar disorder ( n = 226), a population control group ( n = 252), and psychiatric inpatients of any diagnosis ( n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating hormone level, previously diagnosed hypothyroidism, or both. Subjects were compared with attention to age, gender, and exposure to lithium. Results: The TPO-Abs were more prevalent in bipolar patients (28%) than population and psychiatric controls (3–18%). The presence of TPO-Abs in bipolar patients was associated with thyroid failure, but not with age, gender, mood state, rapid cycling, or lithium exposure. Thyroid failure was present in 17% of bipolar patients and more prevalent in women. It was associated with lithium exposure, especially in the presence of TPO-Abs, but not with current rapid cycling, although an association may have been masked by thyroid hormone replacement. Conclusions: Thyroid autoimmunity was highly prevalent in this sample of outpatients with bipolar disorder and not associated with lithium treatment. These variables appear to be independent risk factors for the development of hypothyroidism, especially in women with bipolar disorder.

Background: Studies suggest that lithium may have profound immunomodulatory effects in animal models as well as in humans. Methods: In this study, whole blood cultures from normal control subjects were established for 5 days and the effects of lithium on cytokine production were investigated. Because many of lithium's actions have been postulated to be modulated through phosphoinositide (PI), protein kinase C (PKC) and cyclic adenosine monophosphate (c-AMP) signaling pathways, the effects of myo-inositol and prostaglandin E 2 , alone or in combination with lithium, were also investigated. Results: We found that lithium caused an increase in interleukin-4 and interleukin-10 levels, traditionally classified as T-helper lymphocyte type-2 cytokines, and a decrease in interleukin-2 and interferon-γ levels, traditionally classified as T-helper lymphocyte type-1 (TH-1) cytokines. This shift cannot be fully explained by lithium's actions on the PI, PKC, or c-AMP messenger systems. Conclusions: Monocytes exposed to lithium in the presence of a mitogen for 5 days produced a shift toward the production of TH-2 cytokines and away from the production of TH-1 cytokines. The study suggests that lithium may have complex time-dependent effects on immune function.

Clinical studies over the years have provided evidence that monoamine signaling and hypothalamic-pituitary-adrenal axis disruption are integral to the pathophysiology of bipolar disorder. A full understanding of the pathophysiology from a molecular to a systems level must await the identification of the susceptibility and protective genes driving the underlying neurobiology of bipolar disorder. Furthermore, the complexity of the unique biology of this affective disorder, which includes the predisposition to episodic and often progressive mood disturbance, and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our progress to date. Imaging studies in patient populations have provided evidence of a role for anterior cingulate, amygdala, and prefrontal cortex in the pathophysiology of bipolar disorder. More recent research strategies designed to uncover the molecular mechanisms underlying our pharmacologic treatments and their interaction in the regulation of signal transduction as well as more advanced brain imaging studies remain promising approaches. This experimental strategy provides data derived from the physiologic response of the system in affected individuals and addresses the critical dynamic interaction with pharmacologic agents that effectively modify the clinical expression of the pathophysiology.

Recent preclinical studies have shown that lithium (Li) robustly increases the levels of the major neuroprotective protein, bcl-2, in rat brain and in cells of human neuronal origin. These effects are accompanied by striking neuroprotective effects in vitro and in the rodent central nervous system in vivo. We have undertaken the present study to determine if lithium exerts neurotrophic/ neuroprotective effects in the human brain in vivo.Using quantitative proton magnetic resonance spectroscopy, N-acetyl-aspartate (NAA) levels (a putative marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medication-free bipolar affective disorder patients and 9 healthy volunteers). Regional brain NAA levels were measured at baseline and following 4 weeks of lithium (administered in a blinded manner).A significant increase in total brain NAA concentration was documented (p.0217). NAA concentration increased in all brain regions investigated, including the frontal, temporal, parietal, and occipital lobes.This study demonstrates for the first time that Li administration at therapeutic doses increases brain NAA concentration. These findings provide intriguing indirect support for the contention that chronic lithium increases neuronal viability/function in the human brain, and suggests that some of Li's long-term beneficial effects may be mediated by neurotrophic/neuroprotective events.

Background: Studies of family history and lithium response in patients with bipolar affective disorder have produced mixed results, but the majority have shown relationships between the presence of affective disorder among relatives and positive responses to lithium in probands. The analysis presented here sought to confirm and to further characterize such relationships. Methods: Subjects described here participated in a long-term, prospective follow-up; had a history of Research Diagnostic Criteria manic disorder or schizoaffective disorder, manic type; and took lithium for periods of 26 weeks or longer. The majority participated in a family study in which first-degree relatives were directly interviewed. Morbidity during lithium and during anticonvulsant trials was quantified in alternative ways, as were the risks among first-degree relatives for bipolar I and nonbipolar affective disorders. Results: Familial loading for bipolar affective disorder was not associated with better outcomes during lithium treatment. Rather, the presence of major depressive disorder (MDD) among relatives was associated with slower improvement during acute treatment and with higher symptom levels during continuing treatment. Findings for morbidity during anticonvulsant treatment were similar. The patients who experienced symptom persistence with lithium did so as well during periods of anticonvulsant treatment and during periods without thymoleptics. Conclusions: A family history of MDD may have an enduring and negative prognostic significance that manifests across treatment conditions. Though difficult to reconcile with several earlier studies, these findings invite replication and further exploration.

Background: The clinical effectiveness of lithium may be due to its decreasing the intracellular concentration of myo-inositol and increasing that of its inositol monophosphate precursors, which is known as the inositol depletion hypothesis. Methods: Magnetic resonance spectroscopy (MRS) was used to measure the concentration of both myo-inositol (1H MRS) and phosphomonoesters (PME) [31P MRS], in healthy volunteers in a double-blind placebo-controlled study. MRS measurements were made at baseline, again on the 7th day of lithium (1200 mg, n = 10) or placebo (n = 6) administration, and again on day 8, 2 hours following oral administration of 20 mg dextroamphetamine to stimulate the phosphoinositol (PI) cycle. Results: Subjects who received lithium showed a greater increase in PME ratios in response to amphetamine administration than did placebo-treated subjects. Conclusions: The present results support the hypothesis that lithium administration blocks the conversion of inositol monophosphates to myo-inositol, and that this effect is especially apparent following PI cycle stimulation. The effects of lithium treatment on myo-inositol in healthy volunteers in vivo are uncertain, and may have to await improvements in the ability to measure myo-inositol in the brain. Keywords: Lithium, inositol, bipolar disorder, amphetamine, magnetic resonance spectroscopy

Recent advances in cellular and molecular biology have resulted in the identification of two novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells of human neuronal origin, and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bcl-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in Alzheimer's disease). Consistent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long term beneficial effects in the treatment of mood disorders via underappreciated neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence of other adequate treatments, the potential efficacy of lithium in the long term treatment of certain neurodegenerative disorders may be warranted.

Background: The interaction between lithium, a mood stabilizer, and the thyroid axis has been extensively studied; however, the regulation of thyroid hormone receptors by lithium is yet to be investigated. Methods: To test whether lithium affects thyroid hormones at the receptor level, we examined the effects of lithium in combination with triiodothyronine (T3) on gene expression of thyroid hormone receptor isoforms in GH3 and B103 cells. Results: The pattern of expression as well as the magnitude of regulation of the different thyroid hormone receptor isoforms appeared to be cell line specific. Whereas T3 regulated all four isoforms in GH3 cells at both time points, T3 did not alter thyroid hormone receptor TRα1 and TRα2 mRNA in B103 cells. Addition of lithium to thyroid hormone-deficient GH3 cells decreased TRα1, α2, and β2 expression without affecting TRβ1 expression at 2 but not 5 days. Addition of lithium to T3-treated GH3 cells did not further modulate gene expression of TRα1, α2, β1, or β2 when compared to cells treated with T3 alone. The effects of lithium in B103 cells appeared to be isoform specific as well as time dependent, since TRα1 expression was selectively decreased in B103 cells, when treated with T3 in the presence of lithium. Conclusions: The present study provides direct evidence that T3 and/or lithium regulate TR gene expression in vitro in a both time-dependent and cell line-specific manner.

Background: This study investigated the effects of catecholamine depletion with alpha-methylparatyrosine (AMPT) on mood indices in patients with bipolar disorder who were in long-term remission with lithium therapy. Methods: Eight subjects with DSM-IV bipolar disorder currently in remission for >3 months on lithium were included in the study. Subjects were given either AMPT or placebo, in a randomized double-blind manner, in two test sessions of 4 days each. Results: Subjects did not have any significant changes in mood during AMPT or placebo administration; however, 24–48 hours after the last active AMPT dose subjects had a transient relapse of hypomanic symptoms. Relapse of hypomanic symptoms did not correlate with increases in serum levels of homovanillic acid or 3-methoxy-4hydroxyphenylglycol. Conclusions: These findings suggest that the mechanism of prevention of manic relapse by long-term lithium therapy may be dependent on stability of the catecholamine system.

Background: A considerable percentage of patients with bipolar disorder do not respond or do not tolerate conventional treatment. Cholinesterase (ChE) inhibitors have been suggested to possess depressogenic and antimanic properties. Methods: We report a case series of treatment-resistant bipolar patients (n = 11) to whom we administered the ChE inhibitor donepezil. Four patients met criteria for current manic episode, 5 for mixed episode, 1 for hypomanic episode, and 1 for major depressive episode. Donepezil was added to current medication on an open-label basis. Ratings were based on a retrospective chart review. Results: Of the 11 patients, 6 (54.5%) demonstrated marked improvement (improvement in CGI-S ≥ 2), 3 (27.2%) demonstrated slight improvement, 1 did not respond, and 1 did not tolerate the medication. Among those patients who had marked improvement (i.e., responders, n = 6), improvement was observed within 2 weeks or less in 5 of them (83%). Patients experienced only minor side effects. Conclusions: These pilot data suggest the efficacy and safety of donepezil in the treatment of bipolar disorder. To our knowledge this is the first published report on the use of donepezil in the treatment of mood disorders. Controlled, randomized, double-blind studies are necessary to validate these preliminary observations.

Background: Serotonergic (5-HT) dysfunction has been hypothesized in mania; however platelet studies on the 5-HT uptake rate and the 5-HT transporter have revealed inconsistent results. To the best of our knowledge no studies have been conducted on the 5-HT 2 receptor status in mania. Methods: We determined density (B max ) and dissociation constant (K d ) of 5-HT 2 receptors in the platelets of 29 normal control and 29 manic subjects using 125 I-ketanserin as the binding radioligand. The manic patients were assessed for the same after 14 days of treatment with lithium ( n = 14) and after return to premorbid levels of functioning ( n = 5). Results: There were no significant differences in the B max (3.51 ± 3.04 vs. 3.14 ± 3.44 fmol/mg protein, p = ms) values between normal control and manic subjects. In comparison to the baseline values B max at day 14 (3.49 ± 3.68 vs. 2.18 ± 1.90 fmol/mg protein, p = ns) and following recovery (1.17 ± 0.85 vs. 1.29 ± 1.13 fmol/mg protein, p = ns) did not show any significant difference. Conclusions: Our findings preliminarily suggest that the platelet 5-HT 2 receptor is neither a state marker nor a trait marker in mania; however studies on the 5-HT 2 receptor using positron-emission tomography ligands will help in conclusively ruling out the involvement of this receptor in mania.

Background: Abnormalities in cell membrane processes and intracellular signal transduction pathways may be implicated in the pathophysiology of bipolar disorder. In this study, we attempted to investigate, in euthymic bipolar patients: 1) in vivo signal transduction abnormalities of the phosphatidylinositol pathway in platelets; and 2) possible in vivo effects of lithium treatment on platelet membrane phospholipids. Methods: We determined the relative absorbances of eight individual classes of platelet membrane phospholipids, using two-dimensional thin-layer chromatography in high-performance plates, followed by scanning laser densitometry, in a group of 10 lithium-treated euthymic bipolar patients and 11 normal controls. Results: The mean relative absorbance of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) was lower in the patient group (0.29 ± 0.08% vs. 0.39 ± 0.12%; t = 2.35, df=19, p = .03); no significant differences between patients and controls were found for the other phospholipids. Conclusions: This study provides in vivo evidence that bipolar patients on lithium treatment exhibit a decreased relative amount of PIP 2 in the platelet cell membranes compared to normal controls.

Background: It is unclear whether there is a relationship between lithium administration and vitamin B12 metabolism. Methods: We compared serum B12, serum folate, and red blood cell folate concentrations in patients receiving and not receiving lithium at two Mood Disorders Clinics. As the two centers differed in vitamin assay methods, data were first analyzed separately and then combined. To rule out an in vitro effect of lithium on the assays, we also added varying amounts of lithium to lithium-free blood samples and measured vitamin concentrations. Results: Mean serum B12 concentrations were approximately 20% lower in the lithium than in the nonlithium group at each center. This difference was statistically significant for each center and on combination (two-tailed p = .017, .021, and .0009). The parametric effect size for each center and the combined weighted mean effect size were moderate in magnitude (.605, .523, and .565). There was a nonsignificant trend toward an increased prevalence of assay-defined B12 deficiency in the lithium group at one center only, with no cases in either group at the other center and a nonsignificant combined relative risk. Conclusions: Our data may represent a lithium-associated decrease in serum B12 concentration. The clinical significance of these findings is not yet clear.

In recent years, there has been considerable excitement about the possibility that the “molecular medicine revolution” would lead to identification of numerous putative targets designed to slow the atrophic/degenerative process in various neuropsychiatric disorders. Indeed, tremendous progress was made in the identification of cellular processes and pathways involved in numerous degenerative diseases; however, to date, proliferation of candidate drugs has not resulted in viable novel clinical treatments for these devastating disorders (Heemskerk et al., 2002). Ironically, the paper by Bearden and associates in this issue of the journal suggests that an old medication present in our therapeutic armamentarium for half a century, exerts neurotrophic effects not only in animal models, but also in humans. Bearden et al. used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 bipolar patients; 20 lithium-treated, and 28 healthy controls. Their results showed gray matter density was significantly greater in bipolar patients, compared with healthy subjects, in diffuse cortical regions, notably bilateral cingulated and paralimbic cortices, areas utilized in attention, motivation and emotion. Additionally, their data revealed greater gray matter density in the right anterior cingulate in lithium-treated patients relative to the bipolar subjects not taking lithium. Their lithium-treated sample included subjects who were on lithium for varying time durations, at different individual doses. The lack of difference in gray mater density between the untreated patients and healthy controls, as well as growing evidence that lithium exerts major effects on a number of cellular proteins and pathways (vide infra) known to regulate cell atrophy/death lends support to the view that gray matter enlargement is mediated through the trophic actions of lithium in the brain.

Background: High rales of thyroid axis abnormalities have been reported in most studies of patients with rapid-cycling bipolar disorder. Mixed states share similarities with rapid-cycling, including close temporal occurrence of manic and depressive symptoms, predominance in women, poor outcome, and less robust response to lithium compared with pure mania: however, thyroid axis abnormalities have not been well studied in mixed mania. Methods: To test the hypothesis that mixed states are associated with a higher prevalence of hypothyroidism than pure mama, immunorcactive triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) concentrations were determined from serum obtained at the time of admission in 37 consecutive patients with DSM-HI-R bipolar disorder, manic or mixed. Results: The mean TSH concentration was significantly higher, and the mean T4 concentration was significantly lower in patients with mixed mania compared with pure mania. There were no significant differences in T3 concentration or in previous lithium exposure. Conclusions: These findings suggest thyroid axis dysfunction is more common in bipolar mixed than in bipolar manic patients.

To verify the theory that lithium exerts its multiple effects by altering the receptor-mediated G protein's activation, in vitro effects of lithium on agonist-induced guanosine triphosphate (GTP) hydrolysis were examined. The basal GTP hydrolyzing activity in human platelet membranes was decreased nonselectively by either LiCl or NaCl at millimolar concentrations, whereas (-)-epinephrine-stimulated increase in the activity (an index of alpha (2A)-adrenoceptor coupled Gi2 function) was unaltered. Furthermore, the stimulation of high-affinity GTPase activity induced by dopamine, carbachol, and R-N(6)-phenylisopropyladenosine in rat brain membranes (indices of the functional coupling between dopamine D2-like, pirenzepine-insensitive muscarinic, and adenosine A1 receptors and their respective Gi proteins) was substantially unaltered regardless of whether 0.5 mmol/L adenosine 5'-(beta, gamma-imido)triphosphate (i.e., 1.75 mmol/L lithium) was included in the assay mixture or not. These results indicate that lithium does not affect in vitro the receptor-mediated activational process of G proteins, at least not of Gi associated with adenylate cyclase inhibition.

Lithium therapy response and age of onset (AOO) were studied in 98 patients with bipolar affective disorder (BPAD) who were divided into subgroups depending on type of family history of affective disorders. The highest (33.0 years) and lowest (25.5 years) age of onset were found in nonfamilial patients and in familial patients with a first-degree relative of BPAD, respectively. Nonfamilial patients showed the best response to lithium. There were 0.9 episodes/year off lithium compared to 0.3 episodes/year on lithium (an 88% decrease). A poorer response (a 71% decrease; a reduction from 1.39 episodes per year off lithium to 0.65 on lithium) was found in familial patients with a first-degree relative of BPAD. Differences in serum lithium values between the groups could not explain the observed differences. Thus, familial patients showed a more severe manifestation of the disease with an earlier AOO and a lower prophylactic effect of lithium.

Twenty psychiatric patients on lithium medication were examined with 7-Li-magnetic resonance spectroscopy of the brain. Patients on long-term lithium treatment (6 months) were compared with a short-term group who had been taking lithium for between 4 and 8 weeks. Patients met DSM-III-R criteria for either recurrent unipolar depressive disorder (DSM-III-R 296.3x) or schizoaffective disorder, depressive type (DSM-III-R 295.70). The brain:serum lithium ratio was 0.76 +/- 0.26; there was no significant difference between short-term and long-term treatment. In the group of long-term treatment patients there was a positive correlation between lithium dose per day and brain lithium concentration (R = .72, p.01), and between lithium plasma concentration and brain lithium concentration (R = .65, p.05). In the short-term group, however, there was no significant correlation for these parameters. No differences between unipolar and schizoaffective disorder were found.