Novel therapeutic targets in mood disorders: Pentoxifylline (PTX) as a candidate treatment.

Numerous pharmacological treatments for mood disorders are currently available; however, rates of treatment resistance, relapse and recurrence remain high. Therefore, novel treatments acting outside of the conventionally targeted monoamine system are urgently needed to improve patient outcomes. Emerging and converging evidence suggests that immune dysfunction, oxidative stress, impaired cerebral blood flow (CBF) and decreased neurotrophic factors all contribute to mood disorder pathophysiology and are therefore treatment targets of interest. Pentoxifylline (PTX) is a phosphodiesterase inhibitor with potent anti-inflammatory and antioxidant effects, with additional pleiotropic effects that lead to improved CBF and increases in brain derived neurotrophic factor (BDNF) levels. The direct effect of non-specific phosphodiesterase inhibition may also improve alertness and cognitive function through enhancing second messenger systems. Replicated preclinical studies have demonstrated antidepressant-like effects in animal models. Small preliminary clinical trials have demonstrated promising results for antidepressant and procognitive effects, however, have yet to be replicated in larger mood disorder samples. Only one randomized clinical trial (RCT) specifically assessed the effects of adjunctive PTX in major depressive disorder (MDD), showing clinically and statistically significant antidepressant effects compared to placebo. No studies have assessed PTX in bipolar disorder (BD), where inflammation and altered CBF have also been strongly implicated. Taken together, PTX presents as a promising pleiotropic agent with several potential novel mechanisms of action meriting further evaluation in clinical trials to evaluate target engagement, antidepressant, procognitive and mood stabilizing effects.

Pharmacotherapy for depression and bipolar disorder during lactation: A framework to aid decision making.

OBJECTIVE: Breastmilk is recommended as the exclusive source of nutrition for infants younger than 6 months due to the numerous health benefits for both infants and mothers. Although many women are prescribed medications during pregnancy and postpartum, limited data are available to assist women in weighing the benefits compared to the risks of peripartum medication use. The goals of this paper are to discuss the importance of breastmilk for the health of both the mother and infant, evaluate the impact of medication use on women's infant feeding choice, describe the transfer of drugs to breastmilk and infants, and provide a framework for clinicians to support evidence-based counseling for women treated for mood disorders. RECOMMENDATIONS: We recommend early pregnancy counseling to discuss the benefits and risks of medications during breastfeeding. The Surgeon General's Call to Action (2011) highlights the short and long-term negative health effects of not providing breastmilk. Integrating recommendations from the pediatric and obstetric teams allows patients to make decisions based on evidence and reach their infant feeding goals. Databases containing summaries of research findings and pharmacologic properties of the drug of interest are an essential resource for clinicians.

Psychotropic drug use in perinatal women with bipolar disorder.

Optimal dose management of psychotropic drugs during the perinatal period reduces the risk for recurrence of mood episodes in women with Bipolar Disorder. Physiological changes during pregnancy are associated with decreases in the plasma concentrations of the majority of mood stabilizing medications. Regular symptom and drug concentration monitoring for lithium and anticonvulsants with reflexive dose adjustment improves the probability of sustained symptom remission across pregnancy. The elimination clearance trajectory across pregnancy for psychotropics dictates the frequency of laboratory monitoring and dose adjustment. The literature on the pharmacokinetics of lithium, lamotrigine, carbamazepine and atypical antipsychotics during pregnancy and postpartum are reviewed, recommendations for symptom and laboratory monitoring are proposed and recommendations for dose adjustments are presented.

Anterior Cingulate Cortex Glutamatergic Metabolites and Mood Stabilizers in Euthymic Bipolar I Disorder Patients: A Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia. METHODS: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm3) 1H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference. RESULTS: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre. CONCLUSIONS: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD.

Trastorno bipolar, litio y pluridisciplinariedad / Bipolar disorder, lithium and pluridisciplinarity

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Nicotine intake and smoking topography in smokers with bipolar disorder.

OBJECTIVES: Cigarette smoking behavior in bipolar disorder (BPD), including the effects of mood-stabilizing medications, has not been well characterized. METHODS: We compared serum nicotine, nicotine metabolite levels, and smoking topography in 75 smokers with BPD to 86 control smokers (CON). For some comparisons, an additional control group of 75 smokers with schizophrenia (SCZ) were included. RESULTS: There were no differences between the BPD and CON groups in baseline smoking characteristics or serum nicotine or cotinine levels. Fifty-one smokers with BPD (68.9%) were taking one of the following mood stabilizers: valproic acid, lamotrigine, carbamazepine, oxcarbazepine, lithium, or topiramate. The 3-hydroxycotinine-to-cotinine ratio, a marker of cytochrome P450 2A6 (CYP2A6) metabolic activity, was significantly higher in BPD versus CON and versus SCZ (0.68 versus 0.49 versus 0.54; p =0.002). The difference between groups, however, was no longer significant when the analysis was repeated with those taking hepatic enzyme-inducing drugs (carbamazepine, oxcarbazepine, and topiramate) included as a covariate. The time between puffs, or interpuff interval (IPI), was shorter in BPD versus CON by an average of 3.0sec (p<0.05), although this was no longer significant when we removed smokers from the analysis of those taking hepatic enzyme inducers. CONCLUSIONS: Smokers with BPD are not different from CON on most measures of nicotine intake and smoking topography. We found an increased rate of nicotine metabolism in smokers taking mood stabilizers that are hepatic enzyme inducers, including carbamazepine, oxcarbazepine, and topiramate. Smokers with rapid nicotine metabolism might be expected to smoke more intensely to compensate for the more rapid disappearance of nicotine from the blood and brain, and may have more difficulty in quitting smoking, although this requires further study.

[Lithium and its relation with the epithelial sodium channel and aquaporin-2]. / El litio y su relación con la acuaporina-2 y el canal de sodio ENaC.

For more than 40 years lithium has been used to treat bipolar disorder and recent trials suggest a potential efficacy also in the treatment of the amnestic mild cognitive impairment. Lithium is filtered by the glomerulus and 65% - 75% of the filtered amount is reabsorbed along the proximal tubule and in the thick ascending limb of Henle's loop by the Na+, K+, 2Cl- transporter and via paracellular. A small fraction of lithium is reabsorbed in the collecting duct's principal cells through the epithelial Na channel (ENaC) located on the apical side of the cells. Polyuria, renal tubular acidosis and chronic renal failure are the most frequent adverse effects of lithium after 10-20 years of treatment and these alterations can reach to a vasopressin nonresponding form of diabetes insipidus entity called nephrogenic diabetes insipidus. It is believed that the molecular mechanisms of these renal changes are related to a reduction in the number of aquaporin-2 inserted in the apical membrane of the cells. The causes of this are complex. Lithium is a powerful inhibitor of the enzyme glycogen synthase kinase 3ß and this is associated with a lower activity of adenylate cyclase with a reduction in the cAMP levels inside of the cells. The latter may interfere with the synthesis of aquaporin-2 and also with the traffic of these molecules from the subapical site to membrane promoting the impairment of water reabsorption in the distal part of the kidney.

El litio y su relación con la acuaporina-2 y el canal de sodio ENaC / Lithium and its relation with the epithelial sodium channel and aquaporin-2

Desde hace más de cuarenta años que el litio es usado para el tratamiento de la enfermedad bipolar; recientes estudios sugieren también su utilidad en el trastorno cognitivo mínimo tipo amnésico. El litio es filtrado en el glomérulo y un 65-75% del mismo es reabsorbido en el túbulo contorneado proximal y en el asa ascendente de Henle por el transportador Na+, K+, 2Cl- y vía paracelular. Una pequeña fracción del litio entra en las células principales del túbulo colector por medio del canal epitelial de sodio sensible al amiloride (ENaC) localizado en la membrana apical de la célula. Luego de 10- 20 años de tratamiento con litio los enfermos pueden desarrollar poliuria, acidosis tubular e insuficiencia renal crónica que puede terminar en una forma de diabetes que no responde a la arginina vasopresina llamada diabetes insípida nefrogénica. Se cree que estas fallas renales son consecuencias de una reducción en el número de moléculas de acuaporina 2 en la membrana apical. Las causas para esto son complejas. El litio es un poderoso inhibidor de la isoforma beta de la enzima glicógeno sintetasa quinasa y esto está asociado a una menor actividad de la adenilato ciclasa que lleva a una disminución en la concentración intracelular de cAMP. Esto finalmente interferiría con la síntesis de nuevas moléculas de acuaporina 2 y con el tráfico de ellas desde la zona subapical de la célula hacia la membrana celular, causando la disminución en la reabsorción de agua en la parte distal del nefrón.

For more than 40 years lithium has been used to treat bipolar disorder and recent trials suggest a potential efficacy also in the treatment of the amnestic mild cognitive impairment. Lithium is filtered by the glomerulus and 65% - 75% of the filtered amount is reabsorbed along the proximal tubule and in the thick ascending limb of Henle's loop by the Na+, K+, 2Cl- transporter and via paracellular. A small fraction of lithium is reabsorbed in the collecting duct's principal cells through the epithelial Na channel (ENaC) located on the apical side of the cells. Polyuria, renal tubular acidosis and chronic renal failure are the most frequent adverse effects of lithium after 10-20 years of treatment and these alterations can reach to a vasopressin nonresponding form of diabetes insipidus entity called nephrogenic diabetes insipidus. It is believed that the molecular mechanisms of these renal changes are related to a reduction in the number of aquaporin-2 inserted in the apical membrane of the cells. The causes of this are complex. Lithium is a powerful inhibitor of the enzyme glycogen synthase kinase 3β and this is associated with a lower activity of adenylate cyclase with a reduction in the cAMP levels inside of the cells. The latter may interfere with the synthesis of aquaporin-2 and also with the traffic of these molecules from the subapical site to membrane promoting the impairment of water reabsorption in the distal part of the kidney.

Increased subgenual cingulate cortex volume in pediatric bipolar disorder associated with mood stabilizer exposure.

OBJECTIVE: The subgenual cingulate (SGC) cortex has been implicated in the pathophysiology of mood disorders. We sought to study morphometric characteristics of the SGC in pediatric subjects with familial bipolar disorder (BD) compared with healthy controls. METHOD: Twenty children and adolescents with BD (mean age = 14.6 years, 4 females) and 20 healthy age-, gender-, and intelligence quotient-matched controls underwent high-resolution anatomical magnetic resonance imaging. Patients were primarily euthymic and most were taking medications. SGC cortex volumes were determined by manual tracings from a reliable rater, blinded to diagnosis. Analyses of covariance were performed with total cerebral gray matter and age as covariates. RESULTS: No differences were found in SGC volumes between BD subjects and healthy controls. Further analysis revealed that BD subjects with past mood stabilizer exposure had significantly increased SGC volumes compared with BD subjects without mood stabilizer exposure, and compared with controls. The increase was driven by larger bilateral posterior SGC volumes. CONCLUSIONS: Youth with familial BD do not appear to have abnormalities in SGC volume. Mood stabilizer exposure, however, may be correlated with increases in SGC volume.

Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies.

OBJECTIVE: Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes. METHOD: In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine. RESULTS: In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance. CONCLUSION: The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure.

Chronic lithium treatment protects the rat kidney against ischemia/reperfusion injury: the role of nitric oxide and cyclooxygenase pathways.

Ischemia/reperfusion injury is a major problem in renal transplantation. Several evidences represent lithium preconditioning effect against ischemia/reperfusion injury in various tissues. In this study our aim was to investigate the protective effect of chronic lithium administration on renal ischemia/reperfusion injury in rats. Ischemia/reperfusion injury was induced by clamping left renal pedicle for 60 min, 2 weeks after right nephrectomy. Lithium-treated animals received lithium-chloride in drinking water for 30days. In order to investigate the role of nitric oxide (NO) and cyclooxygenase (COX) pathways in renoprotective effect of lithium, N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME, NO synthase inhibitor) and indomethacin (COX inhibitor) were used, respectively. Serum creatinine, blood urea nitrogen and renal histology were assessed 24h after inducing ischemia/reperfusion injury. Dimercaptosuccinic acid scan was also performed 48 h following operation. Chronic lithium treatment in ischemia/reperfusion injury groups significantly decreased creatinine (1.09±0.16 mg/dl), blood urea nitrogen (59.0±13.38 mg/dl), histological damage (7.83%±4.02%) and improved cortical function compared with non-lithium treated animals (4.45±0.44, 176.66±12.24 mg/dl and 83.5%±3.5%, respectively) (P<0.001). Either L-NAME or indomethacin administration partially reversed the protective effect of lithium, while simultaneous blockade of NO and COX pathways completely abolished lithium renoprotective effect. Our results indicate that lithium ameliorates renal ischemia/reperfusion injury through NO and/or COX pathways. We propose that lithium pre-treatment as a simple and practical intervention to boost the renal viability and function after ischemia/reperfusion injury may be promising in the setting of transplantation.

Validating GSK3 as an in vivo target of lithium action.

Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Lithium directly inhibits GSK3 (glycogen synthase kinase 3), a critical regulator of multiple signal transduction pathways. Inhibition of GSK3 provides a compelling explanation for many of the known effects of lithium, including effects on early development and insulin signalling/glycogen synthesis. However, lithium also inhibits inositol monophosphatase, several structurally related phosphomonoesterases, phosphoglucomutase and the scaffolding function of beta-arrestin-2. It is not known which of these targets is responsible for the behavioural or therapeutic effects of lithium in vivo. The present review discusses basic criteria that can be applied to model systems to validate a proposed direct target of lithium. In this context, we describe a set of simple behaviours in mice that are robustly affected by chronic lithium treatment and are similarly affected by structurally diverse GSK3 inhibitors and by removing one copy of the Gsk3b gene. These observations, from several independent laboratories, support a central role for GSK3 in mediating behavioural responses to lithium.

Pharmacokinetic and pharmacodynamic interactions between carbamazepine and aripiprazole in patients with schizophrenia.

Pharmacokinetic and pharmacodynamic interactions between carbamazepine and aripiprazole were studied in 18 inpatients with schizophrenia being treated with aripiprazole. The daily dose of aripiprazole was 24 mg in 15 cases and 12 mg in 3 cases. Carbamazepine 400 mg/d was coadministered for 1 week, and blood samples were taken twice before the start of carbamazepine coadministration and then 1 week after completion. In addition, on these days, the severity of illness and side effects were evaluated using the Positive and Negative Syndrome Scale and the Udvalg for Kliniske Undersøgelser side effects rating scale, respectively. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. Carbamazepine significantly decreased both plasma concentrations of aripiprazole and dehydroaripiprazole by 64% and 68%, respectively (P < 0.001). Despite these decreases in plasma concentrations, the total and negative scores in Positive and Negative Syndrome Scale, together with the neurological score in Udvalg for Kliniske Undersøgelser, decreased slightly but significantly (P < 0.05) after carbamazepine coadministration. The present study implies that carbamazepine augmentation may be effective for patients with schizophrenia treated with aripiprazole, although carbamazepine dramatically decreases plasma concentrations of aripiprazole and dehydroaripiprazole, by inducing the metabolism of these compounds.

The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1.

The mood stabilizing agents lithium chloride (LiCl) and sodium valproate (VPA) have recently gained interest as potential neuroprotective therapeutics. However, exploitation of these therapeutic applications is hindered by both a lack of molecular understanding of the mode of action, and a number of sub-optimal properties, including a relatively small therapeutic window and variable patient response. Human neuroblastoma cells (SH-SY5Y) were exposed to 1 mM lithium chloride or 1 mM sodium valproate for 6 h or 72 h, and transcriptomes measured by Affymetrix U133A/B microarray. Statistically significant gene expression changes were identified using SAM software, with selected changes confirmed at transcript (TaqMan) and protein (Western blotting) levels. Finally, anti-apoptotic action was measured by an in vitro fluorescent assay. Exposure of SH-SY5Y cells to therapeutically relevant concentrations of either lithium chloride or sodium valproate elicited 936 statistically significant changes in gene expression. Amongst these changes we observed a large (maximal 31.3-fold) increase in the expression of the homeodomain protein Six1, and have characterized the time- and dose-dependent up-regulation of this gene in response to both drugs. In addition, we demonstrate that, like LiCl or VPA treatment, Six1 over-expression protects SH-SY5Y cells from staurosporine-induced apoptosis via the blockade of caspsase-3 activation, whereas removal of Six1 protein via siRNA antagonises the ability of LiCl and VPA to protect SH-SY5Y cells from STS-induced apoptosis. These results provide a novel mechanistic rationale underlying the neuroprotective mechanism of LiCl and VPA, suggesting exciting possibilities for the development of novel therapeutic agents against neurodegenerative diseases such as Alzheimer's or Parkinsonism.

Antimanic potency of typical neuroleptic drugs and affinity for dopamine D2 and serotonin 5-HT2A receptors--a new analysis of data from the archives and implications for improved antimanic treatments.

Datasets of antimanic potency ratings and receptor-binding affinities [inhibition constants (K(i))] at dopamine D2 and serotonin 5-HT2A brain receptors were accessed from published literature for a large series (n = 24) of typical neuroleptic drugs, many of which are now obsolete and unobtainable. There was a strong positive association between antimanic potency and affinity for D2 receptors, in support of a 'dopamine-blockade hypothesis' of antimanic drug action. Taking the series of neuroleptics as a whole, there was no association between antimanic potency and affinity for 5-HT2A receptors. Despite this, within a subsample of typical neuroleptics with low affinity for D2 receptors resembling new generation atypical antipsychotics, a positive association between antimanic potency and affinity for 5-HT2A receptors emerged. This suggests that blockade of brain 5-HT2A receptors plays at least a subsidiary role in the antimanic effects of some typical neuroleptics. Other considerations also suggest that combining drugs to achieve high affinity for and blockade of both dopamine D2 receptors and serotonin 5-HT2A receptors, possibly with additional direct or indirect stimulation of postsynaptic 5-HT1A receptors, might maximize antimanic efficacy.

Regulation of brain polyunsaturated fatty acid uptake and turnover.

The brain is particularly enriched in glycerophospholipids with either arachidonic or docosahexaenoic acid esterified in the stereospecifically numbered-2 position. In this paper, we review how combining a kinetic approach to study the uptake and turnover of arachidonic and docosahexaenoic acids within brain phospholipids of unanesthetized rats, along with chronic administration of antimanic drugs (lithium, valproate and carbamazepine), have advanced our understanding of how polyunsaturated fatty acids (PUFA) enter the brain, and the mechanisms that regulate their turnover within brain phospholipids. The incorporation rates of arachidonic and docosahexaenoic acid from the plasma unesterified pool into brain phospholipids closely approximate independent measures of their consumption rates by the brain, suggesting this is quantitatively the major pool for uptake of these PUFA. Antimanic drugs (lithium and carbamazepine) that downregulate the activity of the calcium-dependent cytosolic phospholipase A(2) (cPLA(2)) transcription factor AP-2, and in turn the expression and activity of cPLA(2,) lead to a selective downregulation in brain arachidonic acid turnover. Furthermore, targeting arachidonoyl-CoA formation via ordered, non-competitive inhibition of an acyl-CoA synthetase with valproate also selectively decreases brain arachidonic acid turnover. Drugs that increase brain cPLA(2) activity (N-methyl-d-aspartic acid and fluoxetine) are correlated with increased turnover of arachidonic acid in brain phospholipids. Altered PUFA metabolism has been implicated in several neurological disorders, including bipolar disorder and Alzheimer's disease. Identifying the enzymes that regulated brain PUFA metabolism could lead to new therapeutic approaches for these disorders.