Dissecting disease entities out of the broad spectrum of bipolar-disorders.

The etiopathology of bipolar disorders is yet unraveled and new avenues should be pursued. One such avenue may be based on the assumption that the bipolar broad spectrum includes, among others, an array of rare medical disease entities. Towards this aim we propose a dissecting approach based on a search for rare medical diseases with known etiopathology which also exhibit bipolar disorders symptomatology. We further suggest that the etiopathologic mechanisms underlying such rare medical diseases may also underlie a rare variant of bipolar disorder. Such an assumption may be further reinforced if both the rare medical disease and its bipolar clinical phenotype demonstrate a] a similar mode of inheritance (i.e, autosomal dominant); b] brain involvement; and c] data implicating that the etiopathological mechanisms underlying the rare diseases affect biological processes reported to be associated with bipolar disorders and their treatment. We exemplify our suggested approach by a rare case of autosomal dominant leucodystrophy, a disease entity exhibiting nuclear lamin B1 pathology also presenting bipolar symptomatology.

Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects.

Cumulating evidence for the involvement of mitochondrial dysfunction in psychiatric disorders leaves little to no doubt regarding the involvement of this pathology in mood disorders. However, mitochondrial abnormalities are also observed in a wide range of disorders spanning from cancer and diabetes to various neurodegenerative and neurodevelopmental disorders such as Parkinson's, Alzheimer's, Huntington's, autism, and amyotrophic lateral sclerosis. The apparent lack of specificity questions the role of mitochondrial dysfunction in psychiatric disorders, in general, and in mood disorders, in particular. Is mitochondrial dysfunction a general phenomenon, simplistically rendering brain cells to be more vulnerable to a variety of disease-specific perturbations? Or is it an epiphenomenon induced by various disease-specific factors? Or possibly, the severity and the anatomical region of the dysfunction are the ones responsible for the distinct features of the disorders. Whichever of the aforementioned ones, if any, is correct, "mitochondrial dysfunction" became more of a cliché than a therapeutic target. In this review, we summarize current studies supporting the involvement of mitochondrial dysfunction in different psychiatric disorders. We address the question of specificity and causality of the different findings and provide an alternative explanation for some of the aforementioned questions.

Chronic oral carbamazepine treatment elicits mood-stabilising effects in mice.

OBJECTIVE: The underlying biology of bipolar disorder and the mechanisms by which effective medications induce their therapeutic effects are not clear. Appropriate use of animal models are essential to further understand biological mechanisms of disease and treatment, and further understanding the therapeutic mechanism of mood stabilisers requires that clinically relevant administration will be effective in animal models. The clinical regimens for mood-stabilising drugs include chronic oral administration; however, much of the work with animal models includes acute administration via injection. An effective chronic and oral administration of the prototypic mood stabiliser lithium was already established and the present study was designed to do the same for the mood stabiliser carbamazepine. METHODS: Mice were treated for 3 weeks with carbamazepine in food. ICR mice were treated with 0.25%, 0.5% and 0.75%, and C57bl/6 mice with 0.5% and 0.75%, carbamazepine in food (w/w, namely, 2.5, 5.0 or 7.5 g/kg food). Mice were then tested for spontaneous activity, forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperactivity. RESULTS: Oral carbamazepine administration resulted in dose-dependent blood levels reaching 3.65 µg/ml at the highest dose. In ICR mice, carbamazepine at the 0.5% dose had no effect on spontaneous activity, but significantly reduced immobility in the TST by 27% and amphetamine-induced hyperactivity by 28%. In C57bl/6 mice, carbamazepine at the 0.75% dose reduced immobility time in the FST by 26%. CONCLUSIONS: These results demonstrate a behaviourally effective oral and chronic regimen for carbamazepine with mood stabilising-like activity in a standard model for mania-like behaviour and two standard models for depression-like behaviour.

Lithium, inositol and mitochondria.

Our recent DNA-microarray and proteomics studies searching for pathways affected both by chronic lithium treatment and by knockout of each of two genes (IMPA1 or Slc5a3) encoding for proteins related to inositol metabolism, indicated up-regulation of mitochondria-related genes and autophagy-related proteins in the frontal cortex. Differently from previously reported observations of aberrant mitochondrial function in bipolar patients which leave a causality relationship between mitochondrial dysfunction and bipolar disorder an open question, the behavioral results of our recent report following rotenone treatment tempt us to speculate that mitochondrial dysfunction predisposes manic behavior and that drugs targeted to ameliorate mitochondrial function are potential preventers of bursting manic episodes. However, the promiscuity of the involvement of mitochondrial dysfunction and impaired autophagy in the pathophysiology of psychiatric and neurodegenerative disorders raises questions regarding the credibility and relevance of these findings.

Beware of your mouse strain; differential effects of lithium on behavioral and neurochemical phenotypes in Harlan ICR mice bred in Israel or the USA.

Animal models are crucial components in the search for better understanding of the biological basis of psychiatric disorders and for the development of novel drugs. Research, in general, and research with animal models, in particular, relies on the consistency of effects of investigated drugs or manipulations across experiments. In that context, it had been noted that behavioral responses to lithium in ICR (CD-1) mice from Harlan Israel have changed across the last years. To examine this change, the present study compared the effect of lithium treatment in ICR mice from Harlan Israel with the ICR mice from Harlan USA. The mice were treated with chronic oral lithium. Their lithium serum levels were measured and their behavior in the forced swim test (FST) was evaluated. The mice were also treated with [(3)H]-inositol ICV and lithium injection and their frontal cortex [(3)H]-phosphoinositols accumulation was measured. Results show that lithium serum levels in Israeli mice were significantly lower compared with the USA mice, that lithium had no behavioral effect in the Israeli mice but significantly reduced FST immobility time of the USA mice, and that phosphoinositols accumulation was much more strongly affected by lithium in the USA mice compared with the Israeli mice. These results suggest that the Israeli Harlan colony of ICR mice changed significantly from the original ICR colony in Harlan USA and that the differences might be related to absorption or secretion of lithium.

Inositol-related gene knockouts mimic lithium's effect on mitochondrial function.

The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.

The inositol monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test.

RATIONALE: Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization. OBJECTIVES: The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST). METHODS: The inhibitor was administered intracerebroventricularly in liposomes. RESULTS: L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST. CONCLUSIONS: It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor's effect with intracerebroventricular inositol would be an important further step in proof.

Gene-expression studies in understanding the mechanism of action of lithium.

Lithium salts are among the drugs of choice for the treatment of bipolar disorder. Despite six decades of intensive research and an accumulating number of known cellular targets, lithium's mechanism of action still needs to be unraveled. The evolution of large-scale gene-expression analysis methodologies has provided a promising tool to understand the cellular events underlying the mood-stabilizing effect of the drug. However, despite great improvement achieved in transcriptome studies, findings of genes differentially expressed by lithium treatment exhibit, so far, a low reproducibility rate. This review discusses the different design and data analysis strategies applied in the studies and summarizes the possible reasons for the discrepancies among the reports.

The biology of tryptophan depletion and mood disorders.

The involvement of the serotonergic system in the pathophysiology and treatment of affective disorders has been strongly implicated. The tryptophan depletion paradigm is widely used to study the effect of lowering serotonin levels. However, the effects observed in such studies are inconsistent and sometimes contradictory. The present review summarizes and discusses these discrepancies, emphasizing the importance of methodological details such as acute versus chronic tryptophan depletion, patients diagnosis and disease state: euthymic versus acute phase and previous drug treatment. Acute tryptophan depletion as a predictive test for personalized antidepressant treatment is suggested.