Combined treatment of myo-inositol and d-chiro-inositol (80:1) as a therapeutic approach to restore inositol eumetabolism in patients with bipolar disorder taking lithium and valproic acid.

OBJECTIVE: Patients with bipolar disorder (BD) experience a poor quality of life (QoL) and a weak adherence to the therapy due to the various side effects occurring during the pharmacological therapy. To date clinicians have no tools to intervene on such effects, considering them as an unavoidable part of the therapy. This review paves the way for a step forward in the management of patients with BD bridging the therapeutic gap in clinical practice. MATERIALS AND METHODS: We reviewed the literature, searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including bipolar disorder, lithium and valproic acid, inositol role in bipolar disorder, side effects, inositol depletion, supplementation of inositols under lithium treatment, inositol role in metabolism, hypothyroidism, renal and cardiac functionality. In particular, we narrowed the search down to English literature, excluding works before 1980s. Regarding clinical studies, we included case reports and both preclinical and clinical studies, especially only those exhibiting a control group. The outcome of the database search was to highlight the threat of side effects and the relationship with inositol lower levels, paving the way for a step forward in the management of patients with BD. RESULTS: Based on the collected evidence, the combined administration of myo-inositol (myo-ins) and d-chiro-inositol (d-chiro-ins) is strongly recommended in order to restore levels and metabolism of inositols. Previous studies pointed out the beneficial effects of inositols in recovering pathological conditions, like polycystic ovary syndrome (PCOS), hypothyroidism, weight gain, cardiac functionality, being all these conditions related to the depletion of inositols. Furthermore, a controlled dosage of inositols, up to 6 grams/daily, may reduce the side effects caused by lithium therapy, without hindering its central therapeutic role on patients' mood. CONCLUSIONS: Considering the iatrogenic depletion of inositols, the tailored ratio 80:1 in favour of myo-ins, may become a safe and effective strategy to counteract side effects, by providing a large amount of myo-ins and an adequate one of d-chiro-ins. The clinical dosage of inositols used as dietary supplementation is 4 grams/daily, and it may allow the recovery of the side effects and improve patients' QoL, without reducing the central therapeutic effect of the pharmacological therapy.

Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary.

PURPOSE/BACKGROUND: High risks of neural tube defects and other teratogenic effects are associated with exposure in early pregnancy to some anticonvulsants, including in women with bipolar disorder. METHODS/PROCEDURES: Based on a semistructured review of recent literature, we summarized findings pertaining to this topic. FINDINGS/RESULTS: Valproate and carbamazepine are commonly used empirically (off-label) for putative long-term mood-stabilizing effects. Both anticonvulsants have high risks of teratogenic effects during pregnancy. Risks of neural tube defects (especially spina bifida) and other major malformations are especially great with valproate and can arise even before pregnancy is diagnosed. Standard supplementation of folic acid during pregnancy can reduce risk of spontaneous spina bifida, but not that associated with valproate or carbamazepine. In contrast, lamotrigine has regulatory approval for long-term use in bipolar disorder and appears not to have teratogenic effects in humans. IMPLICATIONS/CONCLUSIONS: Lack of protective effects against anticonvulsant-associated neural tube defects by folic acid supplements in anticipation of and during pregnancy is not widely recognized. This limitation and high risks of neural tube and other major teratogenic effects, especially of valproate, indicate the need for great caution in the use of valproate and carbamazepine to treat bipolar disorder in women of child-bearing age.

Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: Essential review of the literature and case report.

RATIONALE: Valproic Acid is a commonly used psychiatric drug primarily used as a mood stabilizer. Mild hyperammonemia is a Valproic Acid common adverse effect. This report presents an example of treated hyperammonemia on Valproic acid therapy managed with L-carnitine administration in BD patients characterized by sudden vulnerability. PATIENT CONCERNS: We report the case of a 29-year-old man suffering from bipolar disorder (BD) and substance use disorder who exhibited sudden altered mental status upon admittance to the inpatient unit. The patient was started on Valproic acid with no improvement. DIAGNOSES: The patient had remarkably high ammonia levels (594 µg/dL) without hepatic insufficiency, likely due to his valproate treatment. INTERVENTIONS: The patient was administered lactulose, intravenous hydration, and i.v. levocarnitine supplementation 4.5 g/day. OUTCOMES: The administration leads to reduction of ammonia levels to 99 µg/dL within 12 hours upon initiation of carnitine therapy and progressive restore of his mental status within 24 hours. LESSONS: Resolution of hyperammonemia caused by Valproic acid therapy may be enhanced with the administration of L-carnitine. An interesting aspect of this case was how rapidly the patient responded to the carnitine therapy.

Electrolytes: Calcium Disorders.

A normal serum calcium level is 8 to 10 mg/dL. The diagnosis of hypercalcemia (ie, levels 10.5 mg/dL or greater) should be confirmed with an albumin-adjusted or ionized calcium level. The two most common causes of hypercalcemia are hyperparathyroidism and malignancy. Drugs, notably lithium and thiazide diuretics, also can cause hypercalcemia. Patients with severe or symptomatic hypercalcemia should be treated initially with hydration to decrease calcium levels. The evaluation should include a parathyroid hormone (PTH) level. If the PTH level is low, cancer is a likely cause, particularly multiple myeloma, breast cancer, or lymphoma. If the PTH level is normal or elevated, hyperparathyroidism is the likely cause. Symptomatic patients with hyperparathyroidism and patients with certain clinical markers should be considered for surgery. For patients with mild disease, monitoring is an option. Hypocalcemia often is caused by vitamin D deficiency. Symptomatic patients and patients with calcium levels less than 7.6 mg/dL should be treated with intravenous calcium gluconate; concomitant magnesium deficiency should be addressed. There is no evidence that routine calcium and vitamin D supplementation reduces the risk of fractures, but studies have shown that vitamin D supplementation does decrease the number of falls in older adults at risk.

Behavioral improvements in a valproic acid rat model of autism following vitamin D supplementation.

The aim was to identify the effects of early vitamin D supplementation on autism-like behaviors (ASD) induced by valproic acid (VPA, an anti-convulsant and a mood stabilizer) in rats. 10 male Wistar rat pups with prenatal exposure to saline were in control group, and 20 Pups with prenatal exposure to VPA were divided into ASD-N (0.9% saline treated) and ASD-D group (vitamin D 80,000 IU/kg treated) on postnatal day 12. Self-grooming, olfactory habituation/dishabituation, and social interaction tests were conducted to assess social interaction, communication, and repetitive behaviors. Serum 25-hydroxyvitamin D (25(OH)D3) was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results showed that compared with the control group, the ASD-N group exhibited increased self-grooming, and decreased pinning and serum 25(OH)D3. Furthermore, the repetitive behavior of the ASD-N group exhibited a negative linear relationship with serum 25(OH)D3 on PND 42. In conclusion, early vitamin D supplementation in infant rat with ASD induced by VPA significantly improved development and behavior of rats related with ASD.

Increased hippocampal, thalamus and amygdala volume in long-term lithium-treated bipolar I disorder patients compared with unmedicated patients and healthy subjects.

OBJECTIVE: Magnetic resonance imaging (MRI) studies in bipolar I disorder (BD-I) suggest that lithium is associated with increased volumes of cortico-limbic structures. However, more rigorous control of confounding factors is needed to obtain further support for this hypothesis. The aim of the present study was to assess differences in brain volumes among long-term lithium-treated BD-I patients, unmedicated BD-I patients, and healthy controls. METHODS: This was a cross-sectional study with 32 euthymic BD-I patients (16 on lithium monotherapy for a mean of 180 months, and 16 receiving no medication for at least the 2 months prior to the study) and 20 healthy controls. Patients were euthymic (Hamilton Depression Rating Scale [HDRS] <6 and Young Mania Rating Scale [YMRS] <7) and had not taken psychotropic medications other than lithium for at least 6 months. Brain images were acquired on a 1.5 Tesla MRI (Phillips, Amsterdam, The Netherlands) and segmented to generate volumetric measures of cortical and subcortical brain areas, ventricles and global brain. RESULTS: Significant differences were found in the volumes of the left amygdala (P=.0003), right amygdala (P=.030), left hippocampus (P=.022), left thalamus (P=.022), and right thalamus (P=.019) in long-term lithium-treated BD-I patients, compared to unmedicated patients and controls, after multivariable adjustment. No differences were observed in global brain volume or in ventricular size among the three groups. Likewise, there was no correlation between serum lithium levels and the increase in size in the described brain areas. CONCLUSIONS: The structural differences found among the three groups, and specifically those between long-term lithium-treated and unmedicated BD-I patients, indicate increased limbic structure volumes in lithium-treated patients.

A population-based study of the comparative effectiveness of second-generation antipsychotics vs older antimanic agents in bipolar disorder.

OBJECTIVES: Numerous antimanic treatments have been introduced over the past two decades, particularly second-generation antipsychotics (SGAs). However, it is not clear whether such newer agents provide any advantage over older treatments. METHODS: A historical cohort design investigated the nationwide population of outpatients with bipolar disorder treated in the Department of Veterans Affairs who were newly initiated on an antimanic agent between 2003 and 2010 (N=27 727). The primary outcome was likelihood of all-cause hospitalization during the year after initiation, controlling for numerous demographic, clinical, and treatment characteristics. Potential correlates of effect were explored by investigating time to initiation of a second antimanic agent or antidepressant. RESULTS: After control for covariates, those initiated on lithium or valproate monotherapy, compared to those beginning SGA monotherapy, were significantly less likely to be hospitalized, had a longer time to hospitalization, and had fewer hospitalizations in the subsequent year. Those on combination treatment had a significantly higher likelihood of hospitalization, although they also had a longer time to addition of an additional antimanic agent or antidepressant. CONCLUSIONS: The present analysis of a large and unselected nationwide population provides important complementary data to that from controlled trials. Although various mechanisms may be responsible for the results, the data support the utilization of lithium or valproate, rather than SGAs, as the initial antimanic treatment in bipolar disorder. A large-scale, prospective, randomized, pragmatic clinical trial comparing the initiation of SGA monotherapy to that of lithium or valproate monotherapy is a logical next step.

Pharmacological agents under research for the maintenance treatment in bipolar disorder.

The treatment of bipolar disorder is a current challenge for clinicians and despite progress in psychopharmacology, options remain limited and results are often unsatisfactory. Current research focuses on finding new pharmaceutical agents for all phases of bipolar disorder, i.e. mania, bipolar depression and maintenance. Particularly, relapse prevention and longterm stabilization is a major therapeutic target. Combination treatment and polypharmacy are the most common choices concerning relapse prevention. Furthermore, during maintenance phase patients often experience residual mood symptoms, cognitive deficits and functional decline, which altogether illustrate the inadequate effectiveness of existing treatments and the need for new, targeted, effective and safe treatments for bipolar disorder. This review focuses on active agents for maintenance treatment in bipolar disorder investigated during the last 5 years. The compounds under investigation have been tried or tested either as monotherapy or as an add-on treatment in clinical trials that have progressed up to phase 3 or in preclinical models of bipolar disorder. While awaiting the completion of many ongoing studies, the results so far indicate that paliperidone and pregabalin may have a position in the maintenance treatment of bipolar disorder. Additionally, dextromethorphan, which acts primarily as a NMDA antagonist, may be an interesting compound for further study. However, results on memantine, another NMDA antagonist, were not encouraging. The effects of omega-3 fatty acids and cytidine were not superior to placebo, although they both have neurotrophic and neuroprotective properties. Eslicarbazepine, which has antiepileptic action, provided some evidence of efficacy as monotherapy. Regarding preclinical studies in experimental models, the pharmacological agents under investigation seem to follow the neurobiological pathways related to mechanism of action of lithium, which is still the "golden standard" for preventing recurrence in bipolar disorder. Major therapeutic targets are synthetic glucose kinase 3 (GSK-3) and the path of phosphoinositol (IMP), both probably involved in the action of lithium. Furthermore, the role of circadian rhythms maintenance is being studied in preclinical and clinical trials investigating the efficacy and safety of compounds CK-01 and ramelteon, respectively. Research also focuses on pharmacological agents based on epigenetic changes and gene expression modulation, as the inhibitor of histone deacetylase (HDAC). Of note, the development of valid and reliable experimental models for bipolar disorder, which currently remains quite controversial, will contribute to the understanding of the pathogenic mechanisms and the development of new effective treatments. Improving methodology aspects of clinical trials, such as diagnosis, clinical heterogeneity, monitoring time, gender differences and comorbidities, may promote research. Current studies seem promising for the development of novel pharmacological agents in the near future, although there are methodological limitations in the search for the maintenance treatment in bipolar disorder. New therapeutic targets include not only the already known mechanisms of action, but also novel pathophysiological pathways, probably implicated in bipolar disorder.

Reversible weakness and encephalopathy while on long-term valproate treatment due to carnitine deficiency.

We describe a case of a 35-year-old woman who presented with bilateral leg weakness and encephalopathy while on long-term valproate therapy. She was diagnosed with valproate-induced encephalopathy due to carnitine deficiency. Clinical improvement occurred with oral carnitine supplementation. Our case report highlights the importance of considering carnitine deficiency in patients presenting with unexplained neurological signs while on long-term valproate treatment.

Taking the fuel out of the fire: evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders.

BACKGROUND: Inflammation has emerged as a potentially important factor - and thus putative pharmacological target - in the pathology of bipolar disorders. However to date no systematic evaluations of the efficacy of add on anti-inflammatory treatment for the depressive and manic episodes have been carried out. METHODS: Sixteen articles were ultimately identified - by computer searches of databases (including PsycINFO, MEDLINE, and EMBASE), supplemented by hand searches and personal communication - as meeting study inclusion criteria. RESULTS: Anti-manic effects were evaluated in two trials, one of adjunctive n-acetyl cysteine (NAC), one of omega-3 fatty acids (O3FA), and significant improvements only emerged for NAC. Celecoxib had a rapid but short-lived antidepressant effect. Despite limited effects of O3FA on symptoms, imaging data demonstrated alterations in neuronal functioning that might have longer-term therapeutic effects. Evidence was strongest for adjunctive NAC in bipolar depression though conclusions are limited by small sample sizes. LIMITATIONS: Definitive conclusions are limited by the paucity of data, small study sizes, and the variability in methodology used. CONCLUSIONS: Current evidence for aspirin or celecoxib is insufficient though further investigation of the potential of celecoxib in early illness onset is warranted. Variable evidence exists for add-on O3FA though an indication of short-term treatment effects on membrane fluidity and neuronal activity suggest longer follow-up assessment is needed. The strongest evidence emerged for NAC in depression and future studies must address the role of illness duration and patients׳ baseline medications on outcomes. Careful consideration of lithium toxicity in the elderly and renal impaired is essential.

Dentin decalcification during lithium treatment: case report.

Severe dental decay and changes in tooth structure have been reported in association with the use of lithium in Psychiatry, but lithium effects on tooth inorganic composition remain unknown. A 30-year-old woman with bipolar disorder, treated with lithium carbonate presented severe dental decay. Dentin samples from lithium and healthy volunteers were collected and submitted to ionic and ultrastructural analysis. Samples from the lithium patient exhibited irregular peritubular walls and the mineral crystals were irregularly arranged in the intertubular dentin. In addition, a decrease in Mg/P/Ca and an increase of Zn concentrations were detected. These data suggest that the severe dental decay and changes in the tooth structure observed for the lithium-treated patient are related to dentin mineral loss and that this pathological condition is different from caries lesions.

Evidence-based treatment strategies for treatment-resistant bipolar depression: a systematic review.

OBJECTIVES: Treatment resistance in bipolar depression is a common clinical problem that constitutes a major challenge for the treating clinician as there is a paucity of treatment options. The objective of this paper was to review the evidence for treatment options in treatment-resistant bipolar depression, as found in randomized controlled trials and with special attention to the definition and assessment of treatment resistance. METHODS: A Medline search (from database inception to May 2012) was performed using the search terms treatment resistance or treatment refractory, and bipolar depression or bipolar disorder, supplemented with 43 separate searches using the various pharmacologic agents or technical interventions as search terms. RESULTS: Only seven studies met our inclusion criteria. These studies examined the effects of ketamine (n = 1), (ar)modafinil (n = 2), pramipexole (n = 1), lamotrigine (n = 1), inositol (n = 1), risperidone (n = 1), and electroconvulsive therapy (ECT) (n = 2). CONCLUSIONS: The available level I evidence for treatment strategies in resistant bipolar depression is extremely scarce, and although the response rates reported are reassuring, most of the strategies remain experimental. There is an urgent need for further study in homogeneous patient samples using a clear concept of treatment resistance.

[Emotional hyper-reactivity and sleep disturbances in remitted patients with bipolar disorders]. / Perturbations de la réactivité émotionnelle et du sommeil dans les troubles bipolaires en période intercritique.

INTRODUCTION: Emotional reactivity and sleep constitute key dimensions of bipolar disorder. Emotional reactivity referred to emotion response intensity and emotion response threshold. Higher emotion reactivity is described during both mood episodes and periods of remission in bipolar disorder. As well, sleep disturbances are described during both acute episodes and euthymic periods in bipolar disorder. Links between sleep and emotion regulation start to be studied in general population. Interactions between sleep and emotion systems can rely on shared neuronal structures, which involve limbic system. Future research on sleep and emotion regulation relationships is required in bipolar disorder. METHODS: A systematic review of the scientific literature was conducted. Studies on emotional reactivity in bipolar disorder during periods of remission were presented. Sleep studies of bipolar disorder during inter-critical periods were discussed too. Researches on interactions between sleep and emotion regulation in general population were presented. Finally, therapeutic applications focusing on sleep and emotional regulation in bipolar disorder were described. RESULTS: Patients with bipolar disorder display disturbances of sleep and emotion reactivity even during periods of remission. Indeed, bipolar patients display more intense and more labile emotions assessed by self-questionnaires, increase positive attribution to neutral stimuli corroborated by startle reflex, functional changing on imagery studies. Sleep disturbances during inter-critical periods refer to clinical poor sleep quality and to increase time in bed, more frequent nocturnal awaking, more variable sleep-wake patterns assessed by actigraphy and polysomnography. In general population some studies have shown the impact of sleep restriction on emotion dysregulation. F-MRI studies show that healthy participants present increase activation of some structures such as amygdala involved in emotion processing. Deregulation of these areas has already been noticed in previous studies of euthymic bipolar patients without sleep restriction procedure. Considering sleep and emotion processes enhance our understanding of medication action mechanisms. Lithium and sodium valproate reduce melatonin light sensitivity and increased the activity period. It can be postulated that these effects on circadian system can impact sleep regulation. Furthermore, an f-MRI study shows that mood stabilizers can reduce amygdala activation of bipolar patients compared to untreated bipolar patients during an emotional task. Emotion and sleep regulation can be targeted by specific psychotherapy. Interpersonal and social rhythm therapy, cognitive behavioral therapy of insomnia and mindfulness applied to bipolar disorder are presented and discussed. DISCUSSION: Disturbances of sleep and emotional reactivity remain during periods of remission in bipolar disorder. Further research is required to better understand relationships between these two processes in bipolar disorder. Sleep and emotion dysgulations can be targeted by specific psychotherapy. More systematic assessment of sleep an emotional reactivity in remitted bipolar patients can lead to consider and treat this residual symptomatology that could reduce recurrences.

Pharmacologic treatments for pediatric bipolar disorder: a review and meta-analysis.

OBJECTIVE: A growing body of literature has documented pediatric bipolar disorder to be a severely impairing form of psychopathology. However, concerns remain as to the inadequacy of the extant literature on its pharmacotherapy. Furthermore, treatment studies have not been systematically reviewed for treatment effects on core and associated symptoms. Thus, a systematic evaluation and synthesis of the available literature on the efficacy of antimanic pharmacotherapy for pediatric bipolar disorder on symptoms of mania, depression, and attention-deficit/hyperactivity disorder was undertaken. METHOD: A systematic search was conducted through PubMed from 1989 through 2010 for open-label and randomized controlled trials published in English on the pharmacotherapy of pediatric mania. RESULTS: There have been 46 open-label (n = 29) and randomized (n = 17) clinical trials of antimanic agents in pediatric bipolar disorder encompassing 2,666 subjects that evaluated a range of therapeutic agents, including traditional mood stabilizers, other anticonvulsants, second-generation antipsychotics, and naturopathic compounds. This literature has documented that the available armamentarium has different levels of efficacy in the treatment of pediatric mania. Because all psychotropic classes are associated with important adverse effects, a careful risk-benefit analysis is warranted when initiating pharmacologic treatment with any of these compounds. In the limited data available, the effects of antimanic agents on depression and symptoms of attention-deficit/hyperactivity disorder have been, in general, modest. Few studies have evaluated the effects of antimanic agents in children younger than 10 years. CONCLUSIONS: A substantial body of scientific literature has evaluated the safety and efficacy of various medicines and drug classes in the treatment of mania in pediatric bipolar disorder. More work is needed to assess the safety and efficacy of psychotropic drugs in children younger than 10 years, to further evaluate the efficacy of naturopathic compounds, and to further evaluate the effects of antimanic treatments for the management of depression and attention-deficit/hyperactivity disorder.

Assessment of medication adherence in a cohort of patients with bipolar disorder.

INTRODUCTION: This study aimed to identify factors associated with medication adherence in bipolar disorder (BPD) patients. METHODS: EMBLEM is a 2-year, prospective, observational study on the outcomes of BPD patients initiating or changing treatment for a manic/mixed episode. Data were collected at baseline, during the first 12 weeks of treatment (acute phase) and up to 24 months of follow-up (maintenance phase). Adherence was assessed by investigators at every visit. Repeated measures logistic regression analyses identified variables associated with adherence. RESULTS: Of 1,831 patients included in the analysis, 76.6% were adherent and 23.4% were non-adherent with their BPD medication during the maintenance phase. Patients were more likely to be adherent if they had insight into their illness at week 12. Patients were less likely to be adherent if they had cannabis abuse/dependence during the acute phase, work impairment or higher CGI hallucinations/delusions at baseline DISCUSSION: Psychotic symptoms, poor insight, cannabis abuse/dependence and work impairment are negatively related to medication adherence during maintenance therapy of bipolar disorder. Patients with these characteristics may need a different therapeutic approach.

Association between mood stabilizers and hypothyroidism in patients with bipolar disorders: a nested, matched case-control study.

OBJECTIVES: This study investigated whether lithium, carbamazepine, and valproate increased the risk for hypothyroidism using Taiwan's National Health Insurance Dataset. METHODS: The sample included 557 bipolar disorder patients with incident hypothyroidism first diagnosed between 1998 and 2004, and 2,228 sex-, age-, and index date-matched bipolar disorder patients without hypothyroidism from 1996-2004. We compared the use of lithium, carbamazepine, and valproate before the onset of hypothyroidism between the two groups using a conditional logistical regression model. RESULTS: Compared with patients who had never used any of the three mood stabilizers, patients were more likely to have hypothyroidism if they only used carbamazepine [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.07-2.65]; or comedication of lithium and valproate (OR = 2.40; 95% CI: 1.70-3.40), lithium and carbamazepine (OR = 1.52; 95% CI: 1.10-2.08), and three mood stabilizers (OR = 2.34; 95% CI: 1.68-3.25). There was a dose-response relationship between the number of mood stabilizers and risk for hypothyroidism (OR = 1.34, 95% CI: 1.21-1.49) and a significant interaction between lithium and valproate on the risk for hypothyroidism (p = 0.020). CONCLUSIONS: Our findings indicate that lithium, carbamazepine, and valproate may increase the risk for hypothyroidism, particularly if combined, and suggest regular monitoring of thyroid function and monotherapy of mood stabilizers for treating patients with bipolar disorders.

Clinical outcomes and low-dose levocarnitine supplementation in psychiatric inpatients with documented hypocarnitinemia: a retrospective chart review.

BACKGROUND: Metabolic encephalopathy is one of the crucial manifestations of carnitine deficiency. In psychiatric patients, low serum carnitine levels may result from chronic valproate therapy. Despite the widespread use of valproate in psychiatry, neither carnitine deficiency nor supplementation has been studied in a psychiatric population. OBJECTIVE: To describe clinical outcomes in hospitalized psychiatric patients with documented hypocarnitinemia who were receiving oral levocarnitine supplementation. METHOD: Retrospective chart review. RESULTS: In 38 patients with hypocarnitinemia, a low-dose oral levocarnitine supplementation, in association with comprehensive psychiatric therapy, did not result in any adverse psychiatric or medical outcomes, and was associated with overall improved behavioral, cognitive, and motor functioning. Initially all patients had some degree of cognitive impairment, but after correction of carnitine serum levels, scores on the Mini-Mental State Examination (MMSE) improved in most of the patients (mean improvement 5.5 points, P <0.0001), and normalized in 11 cases. This allowed a correction of the diagnosis in 8 of 14 patients who had initially been diagnosed with dementia. African-American patients achieved significantly lower serum carnitine levels and MMSE scores than Caucasian patients with comparable therapy. CONCLUSION: We hypothesize that correction of carnitine depletion, either by levocarnitine supplementation or by valproate dose reduction, may enhance recovery from hypocarnitinemia-associated encephalopathy in psychiatric patients. Our findings also suggest that ethnic traits may affect carnitine bioavailability as well as cognitive outcomes in this clinical context. Further studies of carnitine metabolism and supplementation in psychiatric patients are warranted.

Quetiapine in the treatment of acute bipolar mania: efficacy across a broad range of symptoms.

OBJECTIVE: An ideal antimanic therapy is well tolerated and offers full multidimensional symptom relief. The efficacy of quetiapine in the treatment of acute bipolar mania has previously been established. This post-hoc analysis aims to extend our understanding of quetiapine's antimanic efficacy by evaluating its therapeutic effect across the full spectrum of manic symptoms. METHODS: Patient-level data from four similar, randomized, double-blind, placebo-controlled trials evaluating the efficacy and safety of quetiapine in bipolar disorder patients with DSM-IV acute mania were combined. Two trials investigated quetiapine as monotherapy (twice daily) and two trials assessed the combination of quetiapine with either lithium (Li) or divalproex (DVP). Changes in scores on the total Young Mania Rating Scale (YMRS), and on each of the 11 items comprising the YMRS, were the primary measures of interest in this analysis. Changes in the Supplemental Aggression and Agitation subscales of the Positive and Negative Syndrome Scale (PANSS) were secondary measures analyzed. RESULTS: Quetiapine as monotherapy, or in combination with Li or DVP, was a highly effective treatment for acute mania, as shown by overall change scores in the total YMRS. Patients treated with quetiapine monotherapy exhibited a significantly greater reduction (versus placebo) in YMRS total scores at Day 4 (-3.5 versus -2.2; p=0.021), with an increasing between-group difference reported throughout the duration of the trials at Day 21 (-13.6 versus -7.8; p<0.001) and at study endpoint on Day 84 (-19.0 versus -9.6; p<0.001). Quetiapine was also superior in efficacy to placebo on all categorical (i.e., response and remission rates) and secondary outcome parameters. On each of the 11 YMRS items, including the double-weighted core manic items, quetiapine was significantly superior to placebo (p<0.05). Effect sizes at Day 84 ranged from 0.37 to 0.61. Quetiapine in combination with Li/DVP offered a significant benefit over Li/DVP monotherapy, starting at Day 7 (p<0.05) and continuing to the primary study endpoint on Day 21 (p=0.01). Four of 11 YMRS items improved significantly more on quetiapine combination therapy than on Li/DVP monotherapy. The efficacy of quetiapine in these trials appeared independent of baseline disease severity, the presence of psychosis, and treatment-emergent sedation/somnolence. Quetiapine monotherapy produced significantly greater improvement than placebo on the PANSS Activation and the PANSS Supplemental Aggression Risk subscale scores. Similar findings were obtained with quetiapine combined with Li or DVP. CONCLUSIONS: Patients with bipolar disorder may report severe and complex manic symptoms. The results herein indicate that quetiapine is efficacious across the multiple dimensions of mania, including medically serious symptoms commonly encountered in practice.