Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

General medical burden in bipolar disorder: findings from the LiTMUS comparative effectiveness trial.

OBJECTIVE: This study examined general medical illnesses and their association with clinical features of bipolar disorder. METHOD: Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively. RESULTS: The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14). CONCLUSION: The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.

Predictive value of early improvement in bipolar depression trials: a post-hoc pooled analysis of two 8-week aripiprazole studies.

OBJECTIVE: To evaluate the value of early improvement to predict treatment outcome in patients with bipolar depression. METHODS: Data were pooled from two aripiprazole, 8-week, randomized, double-blind, placebo-controlled trials in patients with bipolar depression without psychotic features to determine whether early improvement (≥20% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score at Week 2 or 3) predicts later response (≥50% MADRS Total score reduction at Week 8) or remission (MADRS Total ≤10 at Week 8). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated (LOCF). Univariate and multivariate logistic regression models were used to evaluate early improvement and baseline demographic/clinical characteristics as predictors of response/remission. RESULTS: In total, 311 patients were randomized to placebo and 306 to aripiprazole. Predictive values of early improvement (≥20% MADRS Total score reduction) for remission with aripiprazole at Week 2/3, respectively, were: sensitivity 83%/94%; specificity 41%/33%; PPV 44%/45%; NPV 81%/91%. The corresponding values with placebo were as follows: sensitivity 70%/84%; specificity 60%/51%; PPV 50%/51%; NPV 77%/84%. Univariate linear regression showed that early improvement (≥15%, ≥20%, ≥25%, ≥30% at Week 3) was a significant potential predictor of remission. CONCLUSION: Absence of early improvement after 3 weeks of treatment reliably predicted non-response/non-remission at study endpoint with high sensitivity and NPV. In patients with <20% improvement after 21 days of aripiprazole monotherapy, treatment should be modified, as continued use is unlikely to result in response/remission. Clinical decision-making to optimize treatment course in bipolar I depression may be appropriate after as little as 2 weeks and certainly within the first 3 weeks of treatment.

Comorbid anxiety and substance use disorders associated with a lower use of mood stabilisers in patients with rapid cycling bipolar disorder: a descriptive analysis of the cross-sectional data of 566 patients.

OBJECTIVE: To study mood stabiliser treatment in patients with bipolar disorder with or without anxiety disorders (ADs) and/or substance use disorders (SUDs). METHODS: Extensive clinical interview and Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid cycling bipolar I (RCBDI) or II (RCBDII), SUDs and ADs. Previous treatment statuses with a mood stabiliser after the first onset of mania/hypomania (unmedicated, mismedicated and correctly medicated) were retrospectively determined in patients enrolled into four similar clinical trials. T-test and chi-square/Fisher's exact were used wherever appropriate. RESULTS: Of 566 patients (RCBDI n = 320, RCBDII n = 246), 46% had any lifetime AD, 67% had any lifetime SUD and 40% had any recent SUD. Overall, 12% of patients were unmedicated, 37% were mismedicated at the onset of first mania/hypomania and 51% were correctly medicated. Presence of lifetime ADs and recent SUDs was associated with fewer mood stabiliser treatments. Patients with RCBDI were more likely correctly medicated than those with RCBDII (OR = 3.64) regardless of the presence (OR = 2.6) or absence (OR = 4.2) of ADs, or the presence (OR = 2.8) or absence (OR = 3.13) of recent SUDs. Presence of lifetime ADs and recent SUDs increased the risk for mismedicated in RCBDI with odds ratios of 1.8 and 1.9, respectively, but not in RCBDII. CONCLUSION: In this multi-morbid cohort of patients with RCBD, 51% of patients (64% of RCBDI and 33% with RCDBII) were correctly medicated with a mood stabiliser after the onset of first mania/hypomania. The presence of ADs and SUDs was associated with an increased risk of mismedicated in patients with RCBDI, but not with RCBDII.

Kainate receptors coupled to the evoked release of [3H]-gamma-aminobutyric acid from striatal neurons in primary culture: potentiation by lithium ions.

The pharmacological properties and modulation by lithium of the kainate (KA) receptor system coupled to the evoked release of [3H]-gamma-aminobutyric acid [( 3H]GABA) from purified populations of striatal neurons in primary culture were examined. KA evoked a dose-dependent (EC50, 100 microM) and saturable increase in [3H]GABA release from striatal neurons that was unaffected by the removal of extracellular calcium and resistant to the actions of tetrodotoxin. The release of [3H]GABA evoked by 100 microM KA was attenuated in a dose-dependent manner by the following excitatory amino acid antagonists (IC50):6-cyano-2, 3-dihydroxy-7-nitroquinoxaline (2 microM),2,3-dihydroxy-6,7-dinitroquinoxaline (2 microM), kynurenate (0.3 mM), and gamma-D-glutamylglycine (2 mM). The antagonist properties of 6-cyano-2,3-dihydroxy-7-nitroquinoxaline, kynurenate, and gamma-D-glutamylglycine were competitive in nature, inducing parallel rightward shifts of the KA dose-response curves. At concentrations at which it did not significantly increase basal levels of [3H]GABA release, quisqualate attenuated in a dose-dependent manner (IC50, 10 microM) the release due to 100 microM KA. The quisqualate receptor agonist alpha-amino-3-hydroxyisoxazolepropionic acid (AMPA), however, exerted a biphasic effect on 100 microM KA-evoked release of [3H]GABA. At lower concentrations of AMPA (0.1-10 microM), the release due to 100 microM KA was potentiated 25-50%; at higher concentrations (greater than 10 microM) AMPA induced a dose-dependent (IC50, 100 microM) attenuation of KA-evoked release. The release of [3H]GABA due to 100 microM KA was significantly potentiated by the replacement of sodium with lithium in the extracellular medium. A significant potentiation (20-30%) was detected with as little as 5-10 mM lithium, and maximal effects (100-110% increase) were obtained with 50-75 mM lithium. Replacement of sodium with choline or N-methyl-D-glucamine could not mimic the actions of lithium. Lithium (25 mM) also induced a 4-fold increase in the levels of endogenous GABA release due to 100 microM KA. Whole-cell voltage-clamp recordings of these striatal neurons indicated that the 100 microM KA-induced inward current was not significantly altered in the presence of 25 mM lithium. Lithium attenuated vasoactive intestinal polypeptide-stimulated cyclic AMP formation by 50%, with a dose dependence similar to that of its actions on KA-evoked release. The results of this study demonstrate a distinct pharmacological profile for the KA receptor system coupled to the evoked release of [3H]GABA from striatal neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Muscarinic receptors and second-messenger responses of neurons in primary culture.

The coupling of muscarinic receptors to second messenger responses was investigated in primary cultures of neurons from the fetal mouse brain. Neurons were maintained in monolayer culture, in serum-free medium; immunocytochemical studies found these cultures to be nearly exclusively neuronal. In striatal cultures, [3H]N-methylscopolamine (NMS) bound specifically and with high affinity (Kd = 70 pM) to a homogeneous population of receptors on intact neurons (320 fmol/mg cellular protein). Displacement of the binding of [3H]NMS by pirenzepine indicated the presence of heterogeneous sites (81% high affinity sites, Kh = 51 nM, K1 = 1.5 microM); AF-DX 116 showed the opposite selectivity (15% high affinity sites, Kh = 56 nM, K1 = 1.3 microM). The dopamine agonist SKF-38393 (1 microM) enhanced the accumulation of cyclic adenosine monophosphate (AMP) in these cultures 2.5-fold; addition of carbachol reduced cyclic AMP levels by 30% (EC50, 1.7 microM). In the presence of 1 mM lithium, carbachol stimulated the accumulation of inositol monophosphate 5-fold (EC50, 61 microM). Both responses were antagonized by pirenzepine (apparent Ki of 23 nM for the phosphoinositide response and 200 nM for the cyclic AMP response) and AF-DX 116 (apparent Ki 540 nM and 160 nM, respectively). In binding studies on brainstem cultures, AF-DX 116 indicated the presence of two sites of approximately equal abundance (Kh = 170 nM, K1 = 2.9 microM); data for pirenzepine were adequately fit by a one-site model (Kd = 630 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Kainate evokes the release of endogenous glycine from striatal neurons in primary culture.

The actions of 56 mM KCl and excitatory amino acid (EAA) agonists on the release of endogenous glycine (Gly) from striatal neurons in primary culture was examined. During a 3 min period, 2 x 10(6) striatal neurons released 743 +/- 51 pmol of Gly. In the presence of 56 mM KCl, an additional 492 +/- 52 pmol of Gly (+66%) were released, 75% of which was dependent upon the presence of extracellular calcium. When striatal neurons were exposed to 1 mM N-methyl-D-aspartate (NMDA) or quisqualate (QA), endogenous Gly released was increased by 370 +/- 71 (+50%) or 120 +/- 31 (+16%) pmol, respectively. In the presence of 1 mM kainate (KA), however, the release of endogenous Gly increased by 994 +/- 82 pmol (+135%). Interestingly, while KA (1 mM) was twice as effective as KCl (56 mM) in evoking the release of endogenous Gly, KCl was 5 times more effective than KA in evoking the release of endogenous gamma-aminobutyric acid (GABA). KA-induced increases of endogenously released Gly were dose-dependent (EC50, 100 microM), saturable and not significantly reduced in the absence of extracellular calcium. The actions of KA were blocked by coincubation with 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX), a competitive antagonist at the KA receptor. These data suggest that the release of endogenous Gly from striatal neurons in primary culture is regulated principally by EAA actions at the KA receptor system.

Neurotransmitter-induced inositol phosphate formation in neurons in primary culture.

Inositol-1,4,5-trisphosphate, produced in cells as a breakdown product of phosphatidylinositol-4,5-bisphosphate, induces, in many cell types, release of calcium from intracellular stores. In murine striatal neurons, differentiated in primary culture, carbachol, norepinephrine, glutamate, and neurotensin stimulate 3H-labeled inositol phosphate (3H-IP) production. The glutamate response was recently characterized as being mediated primarily by receptors of the quisqualate subtype. In the present study, we found that major differences exist between glutamate-stimulated 3H-IP formation and those stimulated by the other neuromediators. The maximal response to glutamate occurred before and during synaptogenesis and declined thereafter, whereas the maximal response to either carbachol or norepinephrine required complete neuronal differentiation. Although the glutamate response appears to be mediated exclusively by direct interaction with the neurotransmitter receptors, responses to carbachol, norepinephrine, and neurotensin were partially or completely blocked by tetrodotoxin.

Dual action of excitatory amino acids on the metabolism of inositol phosphates in striatal neurons.

Glutamate is able to stimulate inositol phosphate (IP) formation in striatal neurons in primary culture, mainly via an excitatory amino acid receptor of the quisqualate subtype. In the present study we show that carbachol (Carb)-(a cholinergic agonist), but not neurotensin or norepinephrine-induced IP production could be reduced by 40% when measured in the presence of Glu. The inhibition of the Carb response by Glu was dose dependent and reproduced by N-methyl-D-aspartate (NMDA). Quisqualate elicited an additive response with Carb. 2-Amino-5-phosphonovalerate (APV) completely reversed the NMDA-induced inhibition. APV had no significant effect on Glu- or kainate-induced inhibition. Therefore, striatal neurons contain at least three different excitatory amino acid receptors: a quisqualate receptor triggering the stimulation of IP metabolism, and an NMDA and a kainate receptor, both able to decrease the Carb-induced IP formation.

Alpha 2-adrenergic receptors mediate inhibition of cyclic AMP production in neurons in primary culture.

The actions of adrenergic agents on the intracellular production of cyclic adenosine monophosphate (AMP) was examined in intact cortical and striatal neurons in primary culture, generated from the fetal mouse brain. Exposure of striatal neurons to the beta-adrenergic agonist isoproterenol (10 microM) resulted in a 5-fold increase in intraneuronal cyclic AMP; norepinephrine (100 microM), alone or in combination with isoproterenol, produced only a 3-fold increase in cyclic AMP levels. However, in the presence of yohimbine (10 microM), cyclic AMP productions due to norepinephrine or isoproterenol plus norepinephrine were identical to isoproterenol alone. When striatal or cortical neurons were exposed to pertussis toxin (100 ng/ml) overnight, there was no detectable difference between isoproterenol- and norepinephrine-stimulated cyclic AMP production. These data suggest that alpha 2-adrenergic receptors mediate the attenuation of cyclic AMP production in neurons and do so via the inhibitory guanine nucleotide regulatory protein of adenylate cyclase.

Release of endogenous amino acids from striatal neurons in primary culture.

Endogenous amino acid release was examined in highly purified striatal neurons obtained from fetal mouse brain, and differentiated in primary culture. This study aimed to determine which amino acids are released from striatal neurons after a brief depolarization period induced by elevated potassium concentration or veratrine. Amino acids released into the extracellular medium, subsequent to a 3-min exposure of striatal neurons, were subjected to HPLC analysis. At 14 days in vitro potassium (56 mM) depolarization elicited a 25-fold increase in gamma-aminobutyric acid release, 85% of which was calcium-dependent. This effect was small but apparent at 7 days in vitro (two-fold increase) and greatly increased between 11 and 14 days in vitro, subsequent to the appearance of synaptic vesicles in nerve terminals. gamma-Aminobutyric acid release was readily reversible within minutes of return to the resting state. Veratrine induced a quantitatively similar but calcium-independent increase in gamma-aminobutyric acid release. Similar results were observed on aspartate and glutamate release, but the increase was very small even after 14 days in vitro (62.2 and 123.3% increase over basal release, respectively). Taurine and hypotaurine release increased during and after depolarization induced by potassium. This effect remained constant between 11 and 18 days in vitro. BAY K 8644, a dihydropyridine-sensitive calcium channel agonist, augmented the effect of 15 mM potassium on gamma-aminobutyric acid release, but this effect remained very small as compared to the potassium (56 mM) or veratrine effects. In addition, nifedipine inhibited this BAY K 8644-induced release. These results demonstrate the high level of differentiation among striatal neurons containing gamma-aminobutyric acid in this in vitro system.

Synaptogenesis of cultured striatal neurons in serum-free medium: a morphological and biochemical study.

Striatal neurons were cultured from the fetal mouse brain and maintained in serum-free medium for 14-21 days in vitro (DIV). Pretreatment of the culture dishes successively with a polycation followed by fetal calf serum resulted in rapid neuron attachment and neurite proliferation. After 9-10 DIV, electron microscope observations revealed the presence of vesicles in axon terminals forming mature synapses with axons and perikarya of adjacent neurons and in varicosities along extended axons. Synapsin I, a synaptic vesicle-specific protein, was present only in neuronal perikarya after 3 DIV, in perikarya and in varicosities along extended axons after 6 DIV, and in varicosities and contact points between axon terminals and adjacent axons or perikarya after 11-14 DIV. Neurotransmitter-stimulated intracellular formation of cAMP decreased markedly during neuronal differentiation. Inositol phosphate formation in response to neurotransmitters, however, increased significantly throughout the period of striatal neuronal development. K+ (56 mM) depolarization resulted in a 2-fold increase in endogenous gamma-aminobutyric acid (GABA) release from striatal neurons, 50% of which was Ca2+-dependent, between 3 and 11 DIV. Between 11 and 14 DIV, subsequent to synapse formation (as revealed by electron microscope observations), GABA release evoked by 56 mM K+ increased up to 5-fold, 75% of which was Ca2+-dependent. It appears that the complete differentiation of striatal neurons in serum-free medium may provide a suitable model for the study of the physiological and regulatory mechanisms involved in nerve cell development.

Serotonin 5-HT1 receptors mediate inhibition of cyclic AMP production in neurons.

In purified striatal and cortical neurons in primary culture, serotonin (5-HT) stimulated basal cyclic AMP production (EC50, 0.5 microM) 2.5- and 1.5-fold, respectively. The 5-HT1 selective agonists, RU 24969 and 8-hydroxy-2-(di-n-propylamino)tetralin (PAT), did not stimulate cyclic AMP production. However, 5-HT, RU 24969 and PAT inhibited VIP-stimulated cyclic AMP formation in a dose-dependent manner. The actions of selective agonists and antagonists at 5-HT receptors mediating attenuation of cyclic AMP production suggest that they may be of the 5-HT1 subtype.

Vasoactive intestinal peptide actions on cyclic AMP levels in cultured striatal neurons.

The actions of vasoactive intestinal peptide (VIP) on intracellular cyclic AMP, in primary cultures of striatal neurons, were examined. VIP stimulated cyclic AMP formation five-fold over basal levels in neurons after 6 days in vitro (DIV); half maximal activation (EC50) was obtained with 10 nM of the peptide. VIP stimulation was both more potent and effective than those due to adrenocorticotropin (ACTH), dopamine (DA) or serotonin (5-HT). VIP efficacy was augmented to 15-20-fold in the presence of 0.1 microM forskolin, which had virtually no effect on cyclic AMP production alone; VIP potency was unaffected. At saturating concentrations of VIP (0.1-1.0 microM), no other agonist can further activate cyclic AMP production. Under these conditions, the interaction with opiate, DA D2 and 5-HT1 receptors, whose activation results in the inhibition of cyclic AMP production, was shown. During the differentiation of striatal neurons, VIP stimulation of cyclic AMP over basal levels, in the presence of 0.1 microM forskolin, decreases progressively from 30-fold after 3 DIV to 11-fold after 10-13 DIV.