On the functions of lithium: The mood stabilizer

Lithium, despite its simple structure, has numerous biological effects. It also has a remarkable therapeutic effect in the prophylactic treatment of manic depression, and is finding a role in controlling aggressive and self-mutilating behavior. The special feature of lithium is that it only acts on overactive systems to bring them back to normal, without affecting the stable system. The mechanisms of action of this simple cation are still largely unknown although the inositol depletion theory is the most widely accepted model. A recent paper⁽¹⁾ described a different molecular mechanism for its effect on development, which may also explain its action in manic depression.     

Enhancing Effects of Chronic Lithium Treatment on Detour Learning in Chicks

Lithium is the first line of therapeutic drugs used to treat both mania and depression in bipolar disorder.Although a body of research suggests that lithium acts as a cognitive enhancer, other animal studies suggest that lithium induces cognitive deficits. Comparatively, the effects of lithium on cognitive behaviour in these studies are inconsistent and contradictory. Further investigations in different species of animals and behavioural tasks are important to evaluate the possibility that lithium may act as a cognitive enhancer. In the present study, the chicks were treated intraperitoneally with lithium chloride (120 mg/kg), and the effects of chronic lithium treatment on chick cognitive behaviour were examined using a detour learning task.Additionally, the effects of chronic lithium treatment on BDNF messenger RNA (mRNA) expression were measured in RTPCR. We found that chronic lithium treatment(120 mg/kg) had no effect on spontaneous motor activity or weight gain of the chicks and that the chicks had a general healthy appearance, while chronic lithium treatment significantly promoted the response latency of detour learning and BDNF mRNA expression. These results suggest that chronic lithium treatment may improve cognitive function.     

Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1

Lithium is used in the clinical treatment of bipolar disorder, a disease where patients suffer mood swings between mania and depression. Although the mode of action of lithium remains elusive, a putative primary target is thought to be inositol monophosphatase (IMPase) activity. Two IMPase genes have been identified in mammals, the well characterized myo-inositol monophosphatase 1 (IMPA1) and myo-inositol monophosphatase 2 (IMPA2). Several lines of genetic evidence have implicated IMPA2 in the pathogenesis of not only bipolar disorder but also schizophrenia and febrile seizures. However, little is known about the protein, although it is predicted to have lithium-inhibitable IMPase activity based on its homology to IMPA1. Here we present the first biochemical study comparing the enzyme activity of IMPA2 to that of IMPA1. We demonstrate that in vivo, IMPA2 forms homodimers but no heterodimers with IMPA1. Recombinant IMPA2 exhibits IMPase activity, although maximal activity requires higher concentrations of magnesium and a higher pH. IMPA2 shows significantly lower activity toward myo-inositol monophosphate than IMPA1. We therefore screened for additional substrates that could be more efficiently dephosphorylated by IMPA2, but failed to find any. Importantly, when using myo-inositol monophosphate as a substrate, the IMPase activity of IMPA2 was inhibited at high lithium and restricted magnesium concentrations. This kinetics distinguishes it from IMPA1. We also observed a characteristic pattern of differential expression between IMPA1 and IMPA2 in a selection of tissues including the brain, small intestine, and kidney. These data suggest that IMPA2 has a separate function in vivo from that of IMPA1.     

Electroconvulsive therapy for manic state with mixed and psychotic features in a teenager with bipolar disorder and comorbid episodic obsessive–compulsive disorder: a case report

Background

Comorbidity of bipolar disorder and obsessive–compulsive disorder is common in adolescence. Obsessive–compulsive disorder symptoms may be episodic and secondary to alterations in mood, and display specific features. Management of pediatric bipolar disorder-obsessive–compulsive disorder is challenging, as pharmacotherapy of obsessive–compulsive disorder may induce or exacerbate manic episodes and there is limited evidence of treatment efficacy. Electroconvulsive therapy is sparsely used in children and adolescents, but is documented to be a safe and efficacious intervention in adults with bipolar disorder. In view of the severity of symptoms in juvenile mania, studies on treatment strategies are warranted. We report a case of an adolescent with bipolar disorder-obsessive–compulsive disorder who was successfully treated with electroconvulsive therapy during an episode of severe mania.

Case presentation

A 16-year-old girl of Middle East origin first presented to us with depressed mood, irritability, and increased obsessive–compulsive disorder symptoms, which were initially interpreted in the context of acute stress secondary to migration. She had been diagnosed with bipolar disorder and obsessive–compulsive disorder in her previous home country, but had difficulties in accounting for earlier psychiatric history. During hospitalization her mood switched to a manic state with mixed and psychotic features, at times showing aggression toward others. Interruption in her lithium treatment for a short period and possibly the introduction of an atypical antipsychotic could in part have been triggering factors. After 8 weeks of in-patient care and psychotropic drug trials, electroconvulsive therapy was initiated and administered every second or third day for 4 weeks, with marked positive response. No apparent side effects were reported.

Conclusions

This case demonstrates the need for a detailed medical history, taking special note of periodicity and character of obsessive–compulsive disorder symptoms, in adolescents with mood disorders. When treating culturally diverse patients, extra consideration should be taken. Special concerns in the pharmacological treatment to avoid the patient’s condition from worsening must be addressed, including giving priority to mood stabilization before obsessive–compulsive disorder symptoms. There are potential benefits in considering electroconvulsive therapy in young patients with severe mania where first-line treatment options have failed.

     

Bipolar disorder: an update

Bipolar disorder (BPD) is one of the most severe forms of mental illness and is characterized by swinging moods. It affects both sexes equally in all age groups and its worldwide prevalence is approximately 3-5%. The clinical course of illness can vary from a mild depression to a severe form of mania. The condition has a high rate of recurrence and if untreated, it has an approximately 15% risk of death by suicide. It is the third leading cause of death among people aged 15-24 years and is a burden on society and families. The pathophysiology of the disorder is poorly understood. However, a variety of imaging studies suggests the involvement of structural abnormalities in the amygdala, basal ganglia and prefrontal cortex. There are two main biological models that have been proposed for depression. These are called the serotonin and norepinephrine hypotheses. Multiple lines of evidence support both of them. It is a life-long disease and runs in families but has a complex mode of inheritance. Family, twin and adoption studies suggest genetic factors but the candidate susceptibility genes, which when mutated can account for a substantial portion of BPD patients, have not yet been conclusively identified. There have been an increasing number of new generation antidepressant drugs developed to treat BPD. However, lithium salt is only the drug that is most efficient in long-term preventive treatment and it also has an anti-suicidal effect. The condition can be well managed by physicians and psychiatrists along with family and patient education. Identification of risk genes in the future may provide a better understanding of the nature of pathogenesis that may lead to a better therapeutic target.     

A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.     

Les médicaments thymorégulateurs et leurs associations dans le traitement des troubles bipolaires

Mood stabilizers are defined by their effectiveness on the various clinical aspects of bipolar episodes (mania, hypomania, depression, mixed states, rapid cycling etc.), and prophylaxis in the long-term course of the disorder. Only a few molecules have a proven efficacy to prevent or limit these disturbances: lithium, carbamazepine, valproic acid, lamotrigine and atypical antipsychotics. In clinical practice polypharmacy is the rule. We have to consider the rationale of these associations.     

A model for the dynamics of bipolar disorders

Bipolar disorders are characterized by recurrent, alternating episodes of mania and depression. To examine the dynamical bases of this cyclical illness we consider a minimal model for bipolar disorders based on the observation that the two poles of the disease are mutually exclusive. We assume that the propensities to mania and depression, which are correlated with the activity of two putative neural circuits that promote, respectively, the manic or the depressive state, inhibit each other. When mutual inhibition is sufficiently strong, the model predicts bistability: the bipolar system is then either in a depressive or in a manic state and can display abrupt switches between these stable states. We consider two simple mechanisms which, when added to mutual inhibition, allow the model to pass from bistability to oscillations. Self-sustained oscillations provide a mechanism for the spontaneous, recurrent switching between mania and depression. The model can generate oscillations with a variety of waveforms, including simple periodic oscillations with comparable or unequal durations of the manic and depressive episodes, or small-amplitude oscillations around one of the two states preceding large-amplitude periodic changes in the propensities to mania or depression. The model provides a theoretical framework that covers the bipolar spectrum, i.e., cycling between the two poles of the disease, or evolution to either mania or depression or to an intermediate state without alternating between the two poles of the disease. The model accounts for the clinical observation that antidepressants can trigger the transition to mania or increase the frequency of bipolar cycling.     

Lithium Reduqes the Accumulation or Inositol Polyphosphate Second Messengers Following Cholinergic Stimulation of Cerebral Cortex Slices

Abstract: The ability of lithium to interfere with the metabolism of inositol phosphates in brain may underlie its therapeutic action in manic-depressive illness. In these experiments, lithium, at therapeutic concentrations, enhanced the accumulation of [³H]inpsitol monophosphate but suppressed the accumulation of the putative second messengers [³H]inositol 1,4,5-trisphosphate ([³H]Ins(1,4,5)P₃) and f³H]inositol 1,3,4,5-tetrakisphosphate following stimulation of cerebral cortex slices with carbachol. Mass measurements of Ins(1,4,5)P₃showed similar inhibitory effects, which could be prevented by preincubation with myo -inositol. These data may reveal the mechanism by which lithium can reduce polyphosphoinositide-midiated neurotransmission in brain.     

Cholinergic involvement in mental disorders.

A recent resurgence of interest in possible cholinergic mechanisms in schizophrenia, mania and depression represents a further extension of the attempt to explain these disorders on the basis of an abnormality in neurotransmission. New emphasis is less on individual neurotransmitters than it is upon their interdependent relationships. The latter is best exemplified by the treatment of Parkinson's disease, which has moved from a cholinergic approach to one that makes important use of dopaminergic mechanisms. Whether or not a reverse shift, from dopaminergic towards cholinergic approaches is justified for treating schizophrenia remains doubtful. Persuasive evidence can be adduced for new approachess to treatments of mania and depression through cholinergic mechanisms. The development of centrally active cholinemimetic agents will permit the clinical testing of some of the hypotheses engendered by this revival of inquiry into the role of acetylcholine in emotional disorders.     

Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function

The central nervous system has the second highest concentration of lipids after adipose tissue. Long chain fatty acids, particularly arachidonic acid and docosahexaenoic acid, are integral components of neural membrane phospholipids. Alterations in neural membrane phospholipid components cannot only influence crucial intracellular and intercellular signaling but also alter many membrane physical properties such as fluidity, phase transition temperature, bilayer thickness, and lateral domains. A deficiency of docosahexaenoic acid markedly affects neurotransmission, membrane-bound enzyme and ion channel activities, gene expression, intensity of inflammation, and immunity and synaptic plasticity. Docosahexaenoic acid deficiency is associated with normal aging, Alzheimer disease, hyperactivity, schizophrenia, and peroxisomal disorders. Although the molecular mechanism of docosahexaenoic acid involvement in the disorders remains unknown, the supplementation of docosahexaenoic acid in the diet restores gene expression and modulates neurotransmission. Also, improvements are seen in signal transduction processes associated with behavioral deficits, learning activity, peroxisomal disorders, and psychotic changes in schizophrenia, depression, hyperactivity, stroke, and Alzheimer disease.     

Mitochondrial Dysfunction and Psychiatric Disorders

Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells. Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders. Tissues with high energy demands, such as the brain, contain a large number of mitochondria, being therefore more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients and after amphetamine administration, an animal model of mania. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Schizophrenia is a devastating mental disorder characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets. Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals. Considering that several studies link energy impairment to neuronal death, neurodegeneration and disease, this review article discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders, like bipolar disorder, depression and schizophrenia.     

Glycogen synthase kinase 3beta as a likely target for the action of lithium on circadian clocks

Although lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder, the mechanisms underlying its therapeutic action are still unclear. Together with its mood-stabilizing effects, lithium is also known to influence the circadian clocks of several organisms including man. Circadian rhythms are altered in patients with bipolar disorder, and it is believed that these rhythms may play an important role in disease mechanisms. It is therefore possible that some of the therapeutic actions of lithium may be related to its effect on circadian clocks. Identifying the targets for lithium's action on circadian clocks would therefore be important both for understanding the mechanisms of its therapeutic effect and also in further understanding disease mechanisms in bipolar disorders. Using Drosophila melanogaster as a model system, we show that long-term administration of lithium results in lengthening of the free-running period (τ) of circadian locomotor activity rhythm of flies in constant darkness (DD). This effect occurs at concentrations similar to the plasma levels of lithium used in the treatment of bipolar disorder. The lithium-treated flies also show reduced activity of one of the previously reported targets of lithium action, Glycogen Synthase Kinase 3β (GSK 3β). GSK 3β has been shown to be involved in the regulation of circadian clocks as the down regulation of this protein results in an elongation of τ. The τ elongation resembles the effect seen with lithium administration in a number of organisms including man, and taken together with the earlier observations our results suggest that lithium inhibits the activity of GSK 3β to produce its effect on circadian clocks.     

Synaptic imbalances in endogenous psychoses

Based on the formalism of logical balance, imbalances of information processing in tripartite synapses are described as a possible explanation for the pathophysiology of endogenous psychoses like depression, mania and schizophrenia. A tripartite synapse consists of the presynapse, the synaptic cleft, the postsynapse (neuronal components) and the glia (glial components). According to the logic of balance in a living system, the number of values and the number of variables must be equal. In a tripartite synapse the neuronal components are interpreted as values, the glial components as variables. In line with this novel synaptic model, three elementary synaptic imbalances can be deduced. First, tripartite synapses are underbalanced if the variables outnumber the values. Such a system state may cause depression. Second, if the values outnumber the variables, the tripartite synapses are overbalanced which may be responsible for mania. Third, if no functional variables are available at all, tripartite synapses process information unbalanced which may cause schizophrenia. The basic symptoms of these psychobiological disorders can be deduced from this novel synaptic model.     

Possible role of prostaglandin E1 in the affective disorders and in alcoholism.

Prostaglandin (PG)E1 may play an important part in the affective disorders, with an excess being present in mania and a deficiency in depression. Platelets from manic patients produce more PGE1 than normal while those from depressive patients produce less. Ethyl alcohol stimulates PGE1 production whereas lithium inhibits it. Alcoholics will tend to have raised PGE1 concentrations while drinking, but, because precursor supplies are limited, when alcohol concentrations fall PGE1 concentrations may fall sharply leading to depression. PGE1 biosynthesis may be affected by nutritional factors including essential fatty acids, pyridoxine, vitamin C, and zinc. Nutritional approaches may be of value in both depression and alcoholism.     

The effects of chronic treatment with mood stabilizers on the rat hippocampal post-synaptic density proteome

Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. There is growing evidence that the disease is correlated with disruptions in synaptic plasticity cascades involved in cognition and mood regulation. Alleviating the symptoms of bipolar disorder involves chronic treatment with mood stabilizers like lithium or valproate. These two structurally dissimilar drugs are known to alter prominent signaling cascades in the hippocampus, but their effects on the post-synaptic density complex remain undefined. In this work, we utilized mass spectrometry for quantitative profiling of the rat hippocampal post-synaptic proteome to investigate the effects of chronic mood stabilizer treatment. Our data show that in response to chronic treatment of mood stabilizers there were not gross qualitative changes but rather subtle quantitative perturbations in post-synaptic density proteome linked to several key signaling pathways. Our data specifically support the changes in actin dynamics on valproate treatment. Using label-free quantification methods, we report that lithium and valproate significantly altered the abundance of 21 and 43 proteins, respectively. Seven proteins were affected similarly by both lithium and valproate: Ank3, glutamate receptor 3, dynein heavy chain 1, and four isoforms of the 14-3-3 family. Immunoblotting the same samples confirmed the changes in Ank3 and glutamate receptor 3 abundance. Our findings support the hypotheses that BPD is a synaptic disorder and that mood stabilizers modulate the protein signaling complex in the hippocampal post-synaptic density.     

Peripheral profiling analysis for bipolar disorder reveals markers associated with reduced cell survival

Little is known about the molecular factors that are altered in remitting bipolar disorder (BD) patients. We carried out proteome profiling of peripheral blood mononuclear cells (PBMCs) and serum from BD patients who were not experiencing mania or major depression (euthymia) compared to matched healthy controls using liquid chromatography–mass spectrometry (LC‐MS^E) and Multi‐Analyte Profiling (Human Map^®) platforms. This resulted in the identification of approximately 60 differentially expressed molecules involved predominantly in cell death/survival pathways. In PBMCs, this was manifested in cytoskeletal and stress response‐associated proteins, whereas most serum analytes were associated with the inflammatory response. The predicted effect of serum analytes on physiological systems was tested by treating PBMCs with serum obtained from the same patients, resulting in reduced cellular survival. These preliminary results suggest that BD patients carry a peripheral fingerprint that has detrimental effects on cell function and that could be used to distinguish BD patients from healthy controls despite being in a remission phase. It is hoped that additional studies of BD patients in the manic and depressed stages could lead to the identification of a molecular fingerprint that could be used for predicting episodic switching and for guiding treatment strategies.     

Chronic Administration of Lamotrigine Downregulates COX-2 mRNA and Protein in Rat Frontal Cortex

Chronic administration to rats of mood-stabilizers that are effective against mania in bipolar disorder, is reported to downregulate markers of the brain arachidonic acid cascade. We hypothesized that chronic administration of lamotrigine, which is used to treat depression and rapid cycling in bipolar disorder, might do so as well. Male CDF rats were administered a therapeutically relevant dose of lamotrigine (10 mg/kg) or vehicle intragastrically once daily for 42 days. Protein levels of isoforms of phospholipase A₂ (PLA₂) and of cyclooxygenase (COX), and the mRNA level of COX-2, were quantified in the frontal cortex using immunoblotting and RT-PCR, respectively. Compared to vehicle-treated rats, chronic lamotrigine significantly decreased frontal cortex protein and mRNA levels of COX-2 without altering protein levels of the PLA₂ isoforms. Consistent with the hypothesis, lamotrigine and other mood-stabilizers have a common downregulatory action on COX-2 expression in rat brain, which may account in part for their efficacy in bipolar disorder.     

抑郁症动物模型的转换研究

据世界卫生组织预测,抑郁症将成为“2020年全球疾病负担”排名第二的重大疾病,防治抑郁症的创新药物研发已成为医药科学发展的重要内容.本文在总结近年来关于抑郁症临床治疗和抑郁症动物模型进展的基础上,围绕“如何提高抑郁症动物模型临床预测效度”这一亟待解决的问题,采用“转化医学”的研究模式,提出关于抑郁症动物模型转换研究的一些策略,以期能为建立临床预测效度高的抑郁症动物模型和创新抗抑郁药物研发的革命性突破奠定基础和提供思路.