Yuly Bersudsky

Homocysteine-Reducing Strategies Improve Symptoms in Chronic Schizophrenic Patients with Hyperhomocysteinemia

Background An elevated homocysteine level is reported to be a risk factor for several diseases, including Alzheimer’s and cerebrovascular disease. Recently, several studies have reported that homocysteine levels are elevated in many schizophrenic patients. Homocysteine levels can be lowered by oral folic acid, B-12, and pyridoxine. Methods Forty-two schizophrenic patients with plasma homocysteine levels >15 μmol/L were treated with these vitamins for 3 months and placebo for 3 months in a study with a randomized, double-blind, placebo-controlled, crossover design. Results Homocysteine levels declined with vitamin therapy compared with placebo in all patients except for one noncompliant subject. Clinical symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale declined significantly with active treatment compared with placebo. Neuropsychological test results overall, and Wisconsin Card Sort (Categories Completed) test results in particular, were significantly better after vitamin treatment than after placebo. Conclusions A subgroup of schizophrenic patients with hyperhomocysteinemia might benefit from the simple addition of B vitamins.

Modulation of Protein Kinase C Isozymes and Substrates by Lithium: The Role of Myo-inositol

Lithium is the most effective treatment for reducing both the frequency and severity of recurrent affective episodes, but despite extensive research, the molecular mechanisms underlying its therapeutic actions have not been fully elucidated. Signal transduction pathways are in a pivotal postion in the central nervous system, able to affect the functional balance between neurotransmitter systems and have clearly been demonstrated to be targets of lithiums actions. We investigate the hypothesis that the action of chronic lithium on PKC isozymes and substrates may be secondary to its potent effect in inhibiting the recycling of inositol. Rats received lithium for 3 weeks and also myoinositol or saline twice daily via intracerebroventricular (ICV) injections. There was a significant interaction between chronic lithium and myo-inositol administration, with the chronic ICV administration of myo-inositol attenuating lithiums effects on PKC α, PKC ε, and on pertussis toxin–catalyzed [32P]ADP-ribosylation. These results suggest that the effects of chronic lithium on signal transduction pathways may stem initially from its inhibition of inositol-1-phosphatase. Given the critical role of PKC isozymes and G proteins in modulating intracellular cross-talk between neurotransmitter systems and thereby the integrative functions of the CNS, future studies using other inhibitors of inositol monophosphatases are warranted, and offer the hope for the development of more potent and more rapidly acting mood-stabilizing drugs.

Inositol treatment raises CSF inositol levels.

Inositol is a key precursor for synthesis of phosphatidylinositol in a major second messenger signalling system. It is biologically active in syndromes such as respiratory distress syndrome but has been thought to be excluded from CNS by the blood-brain barrier. Oral inositol treatment of 8 patients is shown to significantly increase CSF inositol by almost 70%, suggesting possible CNS therapeutic applications of this compound and possible CNS side-effects of systemic therapy.

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1−/−) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1−/− mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1−/− mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1−/− mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1−/− mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial

OBJECTIVES Valproic acids well-known teratogenicity limits its use in women of childbearing age. Valnoctamide is an analog of valproate that does not undergo biotransformation to the corresponding free acid. In mice, valnoctamide has been shown to be distinctly less teratogenic than valproate. Valnoctamide is an anticonvulsant, and we hypothesized that valnoctamide is antimanic. METHODS We performed a double-blind, five-week, add-on, controlled trial of valnoctamide in mania. Patients were treated with risperidone at doses of the physicians discretion. Valnoctamide or placebo was begun at doses of 600 mg/day and increased to 1200 mg after four days. Weekly ratings by a psychiatrist blind to the study drug were conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMRS), and the Clinical Global Impression (CGI). RESULTS Fifteen valnoctamide patients and 17 placebo patients completed at least one post-baseline week and were included in data analysis. In all efficacy measures valnoctamide was more effective than placebo as an add-on to risperidone, using two-way analysis of variance (ANOVA) with time as the within-subject factor. Two-way ANOVA showed a significant effect of time (p < 0.001) and significant interaction between treatment and time (YMRS: p = 0.012; BPRS: p = 0.007; CGI: p = 0.003). Differences between valnoctamide and placebo were significant from week 3 to week 5. CONCLUSION Valnoctamide could be an important valproate substitute for women of childbearing age with bipolar disorder who may become pregnant.

Glycogen synthase kinase-3?? heterozygote knockout mice as a model of findings in postmortem schizophrenia brain or as a model of behaviors mimicking lithium action: negative results

In mice glycogen synthase kinase (GSK)-3&bgr; heterozygote knockout status was reported to cause reduced immobility in the Porsolt forced swim test and reduced amphetamine-induced hyperactivity, behaviors that mimic the effects of lithium. GSK-3&bgr; protein and mRNA level and activity have been reported to be reduced in the postmortem brain of schizophrenia patients and this could suggest the involvement of GSK-3&bgr; in the etiology of schizophrenia. However, apomorphine-induced stereotyping was reported to be unchanged in GSK-3&bgr; heterozygote (HZ) knockout (KO) mice. As such behaviors are not always robust, study in another laboratory seemed indicated. Motor activity and coordination were assessed in the rotarod test. Behavior was studied in the following tests: pilocarpine-induced seizures model for lithium action, Porsolt forced swim test, tail suspension test, elevated plus-maze, large open field, startle response and prepulse inhibition of acoustic startle response, amphetamine-induced hyperactivity, and apomorphine-induced stereotypic climbing. We could not confirm the report that GSK-3&bgr; HZ KO mice exhibit reduced immobility in the Porsolt forced swim or reduced amphetamine-induced hyperactivity in a manner mimicking the behavioral effects of lithium. We did not find increased apomorphine-induced stereotypic climbing or disruption of prepulse inhibition, suggesting that human postmortem findings regarding GSK-3&bgr; in schizophrenia are not mediated by changes in dopamine receptors and are not the cause of prepulse inhibition deficits in schizophrenia. These data do not support the role of GSK-3&bgr; in schizophrenia or in the mechanism of therapeutic action of lithium. Although differences in the genetic background of the GSK-3&bgr; HZ KOs used in the present study compared with that of the previous study could be responsible, such results could suggest that the previously reported effects of GSK-3&bgr; knockout on behavior are not robust.

Curcumin as an Add-On to Antidepressive Treatment: A Randomized, Double-Blind, Placebo-Controlled, Pilot Clinical Study

ObjectivesDepression is a widespread mental disorder in which nearly half of the affected people have recurrent symptoms. Drug combinations may produce cumulative adverse effects, especially in elderly and physically ill patients. It was demonstrated that curcumin possesses antidepressive activity in various animal models of depression, and a combination of curcumin with some antidepressants potentiates the antidepressive effect of these agents. We sought to evaluate the efficacy of curcumin as an antidepressive agent in a combination with other antidepressants in patients with major depression. MethodsForty patients with a first episode of depression participated in a 5-week, double-blind, randomized, placebo-controlled study. The subjects were treated with either 500-mg/d curcumin or placebo together with antidepressants (escitalopram or venlafaxine) during August 2010 until June 2011. The outcome measures were Clinical Global Impression—Severity Scale, Hamilton Depression Rating Scale, and Montgomery-Asberg Depression Rating Scale. ResultsAnalysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. These changes became significant from the first visit after 7 days of treatment. There was no difference between curcumin and placebo, which means negative results. However, the patients in the curcumin group demonstrated a trend to a more rapid relief of depressive symptoms in comparison to those in the placebo group. None of the patients complained of any adverse effect during the study. ConclusionsAlthough there is no definitive proof that curcumin can induce an earlier beneficial effect of antidepressive agents, it seems like an extended study is needed to prove it, using higher therapeutic doses of curcumin.

High-dose peripheral inositol raises brain inositol levels and reverses behavioral effects of inositol depletion by lithium

Lithium (Li) reduces brain inositol levels. Berridge has suggested that this effect is related to Lis mechanism of action. It had previously been shown that pilocarpine causes a limbic seizure syndrome in lithium treated rats, and that these lithium-pilocarpine seizures are reversible by intracerebroventricular inositol administration to rats. We now show that although inositol passes the blood-brain barrier poorly, large doses of intraperitoneal (IP) inositol can also reverse Li-pilocarpine seizures. Using gas chromatography, IP inositol can raise brain inositol levels. Demonstration that inositol enters brain after peripheral administration provides a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle.

A model of inositol compartmentation in astrocytes based upon efflux kinetics and slow inositol depletion after uptake inhibition

Intracellular compartmentation of inositol was demonstrated in primary cultures of mouse astrocytes, incubated in isotonic medium, by determination of efflux kinetics after “loading” with [3H]inositol. Three kinetically different compartments were delineated. The largest and most slowly exchanging compartment had a halflife of ∼9 hr. This slow release leads to retention of a sizeable amount of pre-accumulated inositol in the tissue 24 hr after the onset of uptake inhibition, as confirmed by the observation that the inositol uptake inhibitor fucose caused a larger inhibition of unidirectional inositol uptake than of inositol pool size, measured as accumulated [3H]inositol after 24 hr of combined exposure to the inhibitor and the labeled isotope. Based upon the present observations and literature data, it is suggested that the large, slowly exchanging compartment is largely membrane-associated and participating in signaling via the phosphatidylinositide second messenger system, whereas inositol functioning as an osmolyte is distributed in the cytosol and located in one or both of the compartments showing a faster release.

Inhibition of specific adenylyl cyclase isoforms by lithium and carbamazepine, but not valproate, may be related to their antidepressant effect.

OBJECTIVES Lithium, valproate, and carbamazepine decrease stimulated brain cyclic-AMP (cAMP) levels. Adenylyl cyclase (AC), of which there are nine membrane-bound isoforms (AC1-AC9), catalyzes the formation of cAMP. We have recently demonstrated preferential inhibition of AC5 by lithium. We now sought to determine whether carbamazepine and valproate also preferentially inhibit specific AC isoforms or decrease cAMP levels via different mechanisms. METHODS COS7 cells were transfected with one of AC1-AC9, with or without D1-dopamine receptors. Carbamazepines and valproates effect on forskolin- or D1 agonist-stimulated ACs was studied. The effect of Mg(2+) on lithiums inhibition was studied in membrane-enriched fraction from COS7 cells co-expressing AC5 and D1 receptors. AC5 knockout mice were tested for a behavioral phenotype similar to that of lithium treatment. RESULTS Carbamazepine preferentially inhibited forskolin-stimulated AC5 and AC1 and all D1 agonist-stimulated ACs, with AC5 and AC7 being the most sensitive. When compared to 1 or 3 mM Mg(2+), 10 mM Mg(2+) reduced lithium-induced AC5 inhibition by 70%. In silico modeling suggests that among AC isoforms carbamazepine preferentially affects AC1 and AC5 by interacting with the catechol-estrogen site. Valproate did not affect any forskolin- or D1 receptor-stimulated AC. AC5 knockout mice responded similarly to antidepressant- or lithium-treated wild-types in the forced-swim test but not in the amphetamine-induced hyperactivity mania model. CONCLUSIONS Lithium and carbamazepine preferentially inhibit AC5, albeit via different mechanisms. Lithium competes with Mg(2+), which is essential for AC activity; carbamazepine competes for ACs catechol-estrogen site. Antidepressant-like behavior of AC5 knockout mice in the forced-swim test supports the notion that AC5 inhibition is involved in the antidepressant effect of lithium and carbamazepine. The effect of lithium and carbamazepine to lower cAMP formation in AC5-rich dopaminergic brain regions suggests that D1-dopamine receptors in these regions are involved in the antidepressant effect of mood stabilizers.