Joseph Levine

Increased cerebrospinal fluid glutamine levels in depressed patients

BACKGROUND There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders. METHODS We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects. RESULTS Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression.

The association of the dopamine D4 receptor gene (DRD4) and the serotonin transporter promoter gene (5-HTTLPR) with temperament in 12-month-old infants.

This study examined the association between two common polymorphisms, the dopamine D4 receptor (DRD4) gene and the serotonin transporter promoter (5-HTTLPR) gene and temperament in 61 infants aged 12 months. Twenty-two infants had a least one copy of the 6-8 repeat DRD4 alleles (L-DRD4) and 39 had two copies of the 2-5 repeat allele (S-DRD4). Twenty infants were homozygous for the short form (s/s) of 5-HTTLPR while 41 were either heterozygous for the short and the long form (l/s) or were homozygous for the long form (l/l). The infants were observed in a series of standard temperament episodes that elicited fear, anger, pleasure, interest, and activity. L-DRD4 infants showed less interest in a structured block play situation and more activity in a free play situation. They also displayed less anger in an episode of mild physical restraint. Infants with s/s 5-HTTLPR showed less fearful distress to stranger approach and less pleasure in a structured play situation than infants with l/l or l/s 5-HTTLPR. Duration of looking during block play was affected by a significant interaction between DRD4 and 5-HTTLPR. Shortest duration of looking was associated with the L-DRD4 and s/s 5-HTTLPR genotypes. The implications and limitations of these findings are discussed.

Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review.

BACKGROUND Subsets of psychiatric patients gain excess body weight while receiving mood-stabilizing agents such as lithium carbonate or valproate sodium. Patients who gain excess weight may discontinue therapy, with severe consequences. Among the newer anticonvulsant agents, topiramate is a candidate agent for bipolar disorder and is associated with weight loss when used as adjunctive treatment. OBJECTIVE This open-label, nonrandomized, chart-review study assessed changes in body weight and body mass index (BMI) in patients receiving topiramate, lithium, or valproate. METHODS Data were extracted from the medical charts of patients admitted in 1999 and 2000 to a state psychiatric hospital with either schizophrenia, schizoaffective disorder, bipolar disorder, or other psychiatric diagnoses who were prescribed valproate, lithium, or topiramate and were reviewed for changes in body weight and BMI. The use of concomitant psychotropic medicines was recorded (eg, antipsychotic agents, antidepressant agents, other mood stabilizers such as gabapentin or carbamazepine). Continuous variables were analyzed using a factorial analysis of variance and the Student t test. Contingency statistics were used to analyze categorical variables. RESULTS A total of 214 patients were included in the chart review (123 men, 91 women; mean age, 39.4 years). Significantly more women than men received topiramate (P = 0.004). Patients receiving either lithium or valproate gained a mean (SD) of 6.3 (9.0) kg and 6.4 (9.0) kg, respectively, whereas patients receiving topiramate lost a mean 1.2 (6.3) kg (F = 11.54, df = 2,198; P < 0.001). Lithium- or valproate-treated patients experienced an increase in BMI (mean, 2.1 [3.0] for both groups), whereas topiramate-treated patients experienced a reduction in BMI (mean, -0.5 [2.4]); this result was statistically significant (F = 11.40, df = 2,198; P < 0.001). Finally, lithium- or valproate-treated patients gained >8% of their baseline body weight (8.2% [11.5%] for lithium-treated patients and 8.5% [11.9%] for valproate-treated patients), whereas topiramate-treated patients lost 0.7% (7.2%) of their body weight (F = 9.93, df= 2,198; P < 0.001). CONCLUSIONS Controlled studies for the efficacy of topiramate therapy in various psychiatric conditions are awaited. These data indicate that patients receiving topiramate experience body weight loss and a reduction in BMI. This advantage of topiramate may promote long-term adherence to treatment among psychiatric patients and possibly decrease the medical risks associated with obesity.

Long-term effects of topiramate on bipolar mood instability, weight change and glycemic control: a case-series

Topiramate is an antiepileptic agent, which is being investigated as a mood-stabilizer. Three obese individuals with DSM-IV bipolar I disorder and type II diabetes mellitus received topiramate treatment in combination with antipsychotics and valproate or carbamazepine. In addition to improved mood stability, these individuals lost between 16 to 20.5% of their pre-topiramate body weight and also achieved significant glycemic control.

A post hoc analysis of the impact on hostility and agitation of quetiapine and haloperidol among patients with schizophrenia

BACKGROUND Quetiapine, a drug with a broad pharmacologic profile (similar to that of clozapine), may show benefits for agitation in patients with psychoses. Also, quetiapine may be superior to placebo and either equal or superior to haloperidol in treating this symptom. Available data for other second-generation antipsychotic agents show that quetiapine may have better efficacy in improving agitation compared with haloperidol. OBJECTIVE This reanalysis of a previously reported pivotal clinical trial assessed whether quetiapine or haloperidol has benefits for the treatment of hostility and agitation among patients experiencing an acute exacerbation of schizophrenia. METHODS Patients aged 18 to 65 years of either sex and any ethnicity who had a diagnosis of schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria and who were experiencing an acute exacerbation were recruited into the study. A priori, data from patients assigned to 4 therapeutically effective quetiapine treatment groups (150, 300, 600, and 750 mg) in a previously reported 6-week, double-blind, placebo-controlled clinical trial were combined and compared with data from patients given haloperidol 12 mg or placebo on an agitation measure derived from the Brief Psychiatric Rating Scale (BPRS). Patients who received at least 2 weeks of treatment who had a baseline assessment and at least 1 postbaseline assessment after the 2 weeks of treatment were included. An analysis of variance with the baseline hostility score and center as covariates was used to assess treatment effects of quetiapine or haloperidol versus placebo for changes in agitation scores. A path analysis was used to separate the direct from the indirect effects (via improvements in psychoses and/or overall psychopathology) on agitation scores of quetiapine relative to haloperidol. RESULTS A total of 257 patients (193 men, 64 women) were studied. The combined quetiapine groups comprised 175 patients; the haloperidol group, 42 patients; and the placebo group, 40 patients. Quetiapine treatment reduced agitation scores significantly among patients with acute psychoses compared with placebo. A slight reduction in agitation scores was found when haloperidol treatment was compared with placebo, but this difference was not statistically significant. Compared with haloperidol, quetiapine treatment had a direct and significant effect on agitation that was independent of the improvement in psychotic symptoms. CONCLUSIONS The data in this study suggest that quetiapine treatment has benefits for hostility and agitation among patients experiencing an acute exacerbation of schizophrenia. Furthermore, the path analysis indicated that, relative to haloperidol, quetiapine appeared to have direct effects on agitation that were independent of improvements in psychoses or overall psychopathology, as assessed by the BPRS.

Impact of risperidone on seclusion and restraint at a State Psychiatric Hospital

Objective: To evaluate the impact of risperidone on seclusion and restraint in patients at a state psychiatric facility, shortly after risperidones release. Methods Patients who were in the hospital for at least 3 months prior to receiving risperidone and subsequently received risperidone for at least 3 months formed the cohort. A mirror-image design was used with duration to a maximum of 1 year before and 1 year after initiation of risperidone. The hospital population that did not receive either risperidone or clozapine during the same time period was used for comparison of trends of seclusion and restraint. Results Seventy-four patients (most with schizophrenia) met the inclusion criteria of the risperidone group. There were statistically significant decreases in the number of seclusion hours (2.2 [SD 5.5] to 0.26 [SD 0.06]) and of events (0.23 [SD 0.59] to 0.05 [SD 0.14]) per person per month during risperidone treatment, compared with the prerisperidone treatment period (P = 0.01). The comparison group also evidenced decreases on these measures during the same time period, but the risperidone-treated cohort achieved a proportionally greater reduction. There were similar trends toward reduction in the restraint measures during risperidone treatment compared with prerisperidone, but these did not achieve statistical significance. The comparison group also showed slightly decreased use of restraints over the study period. Conclusions Risperidone appears to have had a positive impact on seclusion in this state-hospital psychiatric population. These data support the positive impact of risperidone on violence found in other studies. Violence and aggression are major factors that affect morale among psychiatric patients and staff. So, any benefit in this regard as a result of antipsychotic drug treatment is salutary for patients, families, and health care providers.

Stability of CSF metabolites measured by proton NMR.

Summary. Analysis of cerebrospinal fluid (CSF) metabolites can provide data regarding CNS involvement in neurologic and psychiatric illness. However, there is lack of research into the effect of processing and storage of CSF specimens on the levels of metabolites analyzed. CSF specimens from 10 depressed patients were analyzed by proton NMR before and after 72 hours exposure to room temperature. No effect of exposure was found on myo-inositol, glucose, acetate, and alanine CSF levels and there was a substantial decrease of citrate (>50%) and increase in lactate, glutamine, creatine, and creatinine levels.

The use of concomitant medications in psychiatric inpatients treated with either olanzapine or other antipsychotic agents: A naturalistic study at a state psychiatric hospital

Concomitant medications are frequently used in the treatment of resistant psychiatric conditions to augment the primary psychotropic agent or to ameliorate side effects. The present study evaluated the prescription of concomitant psychiatric medications for psychiatric inpatients that were prescribed either olanzapine at its first commercial availability or another first-line antipsychotic agent. Sixty-nine newly admitted patients (mainly with schizophrenia) who were prescribed either olanzapine (n = 35) or another first-line antipsychotic agent (n = 34) were assessed (for the prescription of other concomitant psychotropic drugs) before (2-4 weeks prior to study) and following 8 weeks of treatment (unless discharged sooner). The results indicate that significantly fewer olanzapine-treated subjects were prescribed anticholinergic agents as compared to those prescribed other first-line antipsychotic agents, and a similar trend was noted in the prescription of mood stabilizers as well. Olanzapine-treated subjects used less as needed (PRN) antipsychotic medication compared to pre-olanzapine treatment period. Olanzapine-treated subjects used more anxiolytic agents compared to the control group in the early stages of treatment, probably due to the greater baseline severity of illness. These data suggest that olanzapine use is associated with less use of anticholinergic and mood-stabilizing agents as compared to older antipsychotic agents. These results also suggest that there is less need for PRN antipsychotic medication following olanzapine treatment. More severely ill subjects may require more anxiolytics during olanzapine initiation. The need for less anticholinergic and mood-stabilizing agent use with olanzapine could lead to greater adherence to long-term treatment and perhaps decreased cost (i.e. use of blood and organ system monitoring with mood stabilizers). At the end of treatment, olanzapine-treated subjects had statistically significantly lesser concomitant medicine usage compared to control subjects.

Chronicmyo-inositol increases rat brain phosphatidylethanolamine plasmalogen

BACKGROUND Oral myo-inositol (12--18 g/day) has shown beneficial effect in placebo-controlled studies of major depression, panic disorder, and obsessive compulsive disorder, and preliminary data suggest it also may be effective in bipolar depression. Evidence linking antidepressant activity to membrane phospholipid alterations suggested the examination of acute and chronic myo-inositol effects on rat brain membrane phospholipid metabolism. METHODS With both (31)P nuclear magnetic resonance (NMR) and quantitative high-performance thin-layer chromatography (HPTLC; hydrolysis) methods, rat brain phospholipid levels were measured after acute (n = 20, each group) and chronic myo-inositol administration (n = 10, each group). With (31)P NMR, we measured myo-inositol rat brain levels after acute and chronic myo-inositol administration. RESULTS Brain myo-inositol increased by 17% after acute myo-inositol administration and by 5% after chronic administration, as compared with the control groups. Chronic myo-inositol administration increased brain phosphatidylethanolamine (PtdEtn) plasmalogen by 10% and decreased brain PtdEtn by 5%, thus increasing the ratio PtdEtn plasmalogen (PtdEtn-Plas)/PtdEtn by 15%. Phosphatidylethanolamine plasmalogen levels quantified by (31)P NMR and HPTLC were highly correlated. The validity and reliability of the (31)P NMR method for phospholipid analysis were demonstrated with phospholipid standards. CONCLUSIONS The observed alteration in the PtdEtn-Plas/PtdEtn ratio could provide insights into the therapeutic effect of myo-inositol in affective disorders.

Effects of acetyl-L-carnitine and myo-inositol on high-energy phosphate and membrane phospholipid metabolism in zebra fish: a 31P-NMR-spectroscopy study.

Acetyl-l-carnitine (ALCAR) and myo-inositol are reported to enhance motor activity in animal models; modulate membrane phospholipid metabolism (ALCAR and myo-inositol) and high-energy phosphate metabolism (ALCAR) back to normal; and be effective treatments of major depression in humans. Fish in general and zebra fish in particular present unique animal models for the in vivo study of high-energy phosphate and membrane phospholipid metabolism by noninvasive in vivo 31P NMR. This 31P NMR study of free-swimming zebra fish showed that both ALCAR and myo-inositol decreased levels of phosphodiesters and inorganic orthophosphate and increased levels of PCr in the fish. These findings demonstrate both ALCAR and myo-inositol modulate membrane phospholipid and high-energy phosphate metabolism in free-swimming zebra fish.