Epi-Inositol and inositol depletion: Two new treatment approaches in affective disorder

Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epiinositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. We measured the behavior of rats in an elevated plus maze model of anxiety after chronic treatment of 11 daily intraperitoneal injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myoinositol. Lithium has been hypothesized to alleviate mania by reducing brain inositol levels. Inositol in brain derives from the second messenger cycle, from new synthesis, or from diet via transport across the blood brain barrier. Because the first two are inhibited by lithium, we propose that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositol.     

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.     

Reward sensitivity and anger in euthymic bipolar disorder

According to the hypersensitive behavioral approach system (BAS) model of bipolar disorder (BP), hypersensitivity of the BAS is a trait that should be present even in the euthymic state. This would be expected to result in increased anger and reward sensitivity, both of which are related to the approach system. This study examined these predictions through the use of tasks that assess different aspects of the BAS: reward sensitivity, anger and impulsivity. These characteristics were assessed using the probabilistic classification task (PCT), ultimatum game (UG) and single key impulsivity paradigm (SKIP), respectively. Participants were euthymic adult bipolar disorder patients (BP; N=40) and healthy controls (HC; N=41). In the UG, all participants showed the standard pattern of rejecting overtly unfair offers and accepting clearly fair offers; however, BPs rejected more of the moderately unfair offers than did HCs. BP and HC participants did not differ on their ability to learn, but did show different patterns of learning from reward and punishment. Learning for reward and punishment were negatively correlated in the BP group, suggesting that individuals could learn well either from reward or punishment, but not both. No correlation was found between these forms of learning in the HC group. BP patients show signs of their disorder even in the euthymic state, as seen by the dysbalance between reward and punishment learning and their residual anger in the UG.     

Paradoxical hypotony after laser in situ keratomileusis

We present a case of paradoxically low (0 to 2 mm Hg) intraocular pressure (IOP) measured by Goldmann applanation and Tono-Pen tonometry in an eye with corticosteroid-induced high IOP after laser in situ keratomileusis. The patient complained of blurred vision and ocular pain in both eyes. The eyes were firm by palpation, and the IOP measured by Schiotz indentation tonometry was 38 mm Hg. An interface fluid pocket was identified by slitlamp examination, and the corneal surface became steeper. These findings resolved after flap relifting, interface irrigation, and addition of antiglaucoma medications. We postulate that the paradoxically low reading by applanation tonometry was due to fluid accumulation within the flap-bed interface. The applanation tonometry reflected the interface fluid pocket pressure rather than the real high IOP. An exceedingly low IOP should be verified by palpation or by Shiotz indentation tonometry, and interface fluid should be identified.     

Induction of conduction block by Campylobacter jejuni lipopolysaccharides and focal neural insult

A systemic exposure to gram negative LPS have caused transient conduction abnormalities in a certain strain of rats probably associated with the action of cytokines secreted by macrophages. Our previous studies demonstrated that anti-GM1 antibodies induced in rats by the cross-reactive Cj-LPS, caused no conduction abnormalities. We designed the present study to evaluate the effect of systemic exposure to Cj-LPS on nerve conduction after a focal minor neural trauma. Female Lewis rats were sensitized against KLH by repetitive subcutaneous injections. After 28 days rats were intraneurally injected with saline in the right sciatic nerve and concomitantly with intraperitoneal Cj-LPS. Sciatic nerve conduction studies were performed on days 0, 1, 2, 3, and 7 after injections. Nerve conduction blocks developed in all the rats (n=10) which received an intraneural injection of saline concomitantly with the systemic Cj-LPS exposure, before titers of anti-ganglioside antibodies were detected. We conclude that humoral factors (possibly cytokines), other than antibodies are secreted by lymphocytes and macrophages stimulated by gram negative LPS, and cause functional conduction abnormalities when the blood-nerve barrier is disrupted.     

The presence of glia stimulates the appearance of glycinergic synaptic transmission in spinal cord neurons

Previous studies, using electrophysiological and fluorimetric analysis with a calcium sensitive dye, have shown that 5-7 DIV developing spinal cord neurons displayed high levels of glycinergic transmission. GABAergic and AMPAergic neurotransmission contributed much less to the overall transmission. Here, we show that culturing neurons in absence of a glia cell monolayer reduced the frequency of glycinergic spontaneous IPSCs (0.1 +/- 0.01 Hz), without altering the level of overall transmission (3 +/- 1.1 Hz). The predominant transmission was mediated by GABA(A) receptors (72% of total synaptic events). In addition, combination of bicuculline and CNQX blocked synaptically mediated calcium transients recorded with fluo-3. Furthermore, application of glycine revealed the presence of extrasynaptic receptors in these neurons (25 +/- 6 pA/pF). Culturing neurons on a glial cell monolayer increased the frequency of glycinergic currents (0.4 +/- 0.02 Hz), without changing the amplitude of the current (20 +/- 4 pA). The use of a glia-conditioned media reversed the effect of growing the neurons in a glia-deprived condition. These results indicate that the establishment of glycinergic transmission is dependent on the presence of a glia derived soluble factor. However, functional GlyRs were still able to insert in the neuronal membrane in a glia-independent manner.     

Controlled double-blind trial of phenytoin vs. fluoxetine in major depressive disorder

BACKGROUND: Phenytoin was the first non-sedative anticonvulsant introduced and is still the anticonvulsant most widely used worldwide in neurology. Given the efficacy of the anticonvulsant lamotrigine in the depressed phase of bipolar disorder, a critical theoretical question is whether other anticonvulsants used in treating bipolar disorder might be similarly effective. We therefore undertook a controlled trial of phenytoin versus fluoxetine in major depressive disorder. METHOD: Data were collected from July 2001 to July 2003. Thirty-three subjects entered the study. All patients met DSM-IV criteria for major depressive disorder and scored a minimum of 18 on the 24-item Hamilton Rating Scale for Depression (HAM-D) at baseline. After a 3-day washout of any previous medications, patients were randomly assigned to fluoxetine or phenytoin in identical capsules. Each capsule contained phenytoin 100 mg or fluoxetine 7 mg plus cornstarch. Patients started with 1 tablet daily and increased every other day until they were taking 1 tablet 3 times daily with meals. Blood phenytoin levels were taken after 1 week, 3 weeks, and 6 weeks, and dosage was adjusted to achieve blood levels of 10 to 20 microg/mL, to a maximum dose of 4 capsules per day or a minimum dose of 2 capsules per day. Fluoxetine patients were assigned dummy blood phenytoin levels by the control psychiatrist such that the treating physician would raise the number of capsules to at least 3 per day (20 mg of fluoxetine). RESULTS: Thirty-three patients entered the study, and 28 (N = 14 in each treatment group) completed at least 3 weeks and were included in the data analysis. Patients who dropped out after week 3 (3 patients) were included in the study as last value carried forward. There was no difference between treatment groups in overall rate of response or speed of response. CONCLUSION: The absence of a placebo arm in our study allows for the possibility that neither treatment was more effective than placebo. However, the exclusion of past fluoxetine nonresponders and the minimum HAM-D score at baseline of 18 make this possibility unlikely.     

Omega-3 eicosapentaenoic acid in bipolar depression: report of a small open-label study

INTRODUCTION: Epidemiologic studies have suggested that consumption of cold water fish oils may have some protective function against depression. This proposition is supported by a series of biochemical and pharmacologic studies that have suggested that fatty acids may modulate neurotransmitter metabolism and cell signal trans-duction in humans and that abnormalities in fatty acid and eicosanoid metabolism may play a causal role in depression. Aware of the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, we decided to conduct an open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression. METHOD: Twelve bipolar I outpatients with depressive symptoms diagnosed by DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to 6 months. The study was conducted between September 2001 and January 2003. RESULTS: Eight of the 10 patients who completed at least 1 month of follow-up achieved a 50% or greater reduction in Hamilton Rating Scale for Depression scores within 1 month. No patients developed hypomania or manic symptoms. No significant side effects were reported. LIMITATIONS: This study is limited both by the open-label design and by the small sample size. As in all previous reported studies, patients in this study were treated in an outpatient setting, so that the most severely depressed bipolar patients (requiring hospitalization) are not represented. CONCLUSIONS: Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.     

Prophylactic effect of phenytoin in bipolar disorder: a controlled study

Objective:  Phenytoin is an effective anticonvulsant that has not previously been studied prophylactically in bipolar (BP) patients. Thus a study of phenytoin prophylaxis was undertaken and is herein reported.
Method:  Bipolar patients were studied who had at least one episode per year in the previous 2 years despite ongoing prophylaxis. Patients were stable for a mean of 4 months (range 1–13) before entering the study. Phenytoin or placebo was added to their current therapy in a double-blind cross-over design for 6 months in each phase. Thirty observation periods of 6 months each were studied for 23 patients.
Results:  Three patients had relapse on phenytoin and nine had relapse on placebo. There was a significant prophylactic effect of phenytoin in BP disorder [Cox's F -test for comparing survival in two groups: F ( 6 , 18 ) = 3.44, p = 0.02].
Conclusions:  This study suggests prophylactic effects of add-on phenytoin in BP illness. However, the number of patients was small and confirmation is necessary.