Analysis of suicidality in pooled data from 2 double-blind, placebo-controlled aripiprazole adjunctive therapy trials in major depressive disorder.

OBJECTIVE: To assess the impact of adjunctive aripiprazole versus adjunctive placebo treatment on suicidality in patients with major depressive disorder. METHOD: Data were pooled from 2 identical aripiprazole augmentation studies. Patients with DSM-IV-TR-diagnosed major depressive disorder with an inadequate response to 8 weeks of prospective antidepressant treatment were randomly assigned to adjunctive placebo or adjunctive aripiprazole (2-20 mg/d) treatment for 6 weeks. Adverse events related to suicidality were identified in the adverse event database using the Medical Dictionary for Regulatory Activities-preferred term. Treatment-emergent suicidal ideation was defined using item 10 (suicidality) of the Montgomery-Åsberg Depression Rating Scale (MADRS) and item 18 (suicidality) of the Inventory of Depressive Symptomatology (IDS). RESULTS: In total, 737 patients were included in the safety database (aripiprazole n = 371; placebo n = 366). No suicides were reported. There were no treatment-emergent, suicide-related adverse events in the aripiprazole group; 2 patients in the placebo group had ≥ 1 adverse event related to suicide (both suicidal ideation). More placebo than aripiprazole patients > 25 years old experienced a 2-point (P < .01) or 1-point (P < .05) worsening of MADRS item 10 scores. For this age group, 2-point improvement in MADRS item 10 scores and 1-point improvement of IDS item 18 scores were significantly more common in aripiprazole patients than placebo patients (both P < .05). CONCLUSIONS: This post hoc analysis demonstrated that adjunctive aripiprazole treatment in patients with depression with a history of an inadequate response to antidepressant medication is associated with a decreased rate of suicidality in a group of subjects not at significant risk. Prospective trials directly assessing suicidality are needed to further understand the benefits of an adjunctive antipsychotic in an at-risk population. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.

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.

Aripiprazole monotherapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study.

AIMS: Rapid-cycling bipolar disorder is difficult to treat and associated with greater morbidity than non-rapid-cycling disease. This post hoc analysis evaluated 28 patients with rapid-cycling bipolar I disorder from a 100-week, double-blind, placebo-controlled study assessing long-term efficacy, safety and tolerability of aripiprazole in patients with bipolar I disorder (most recently manic/mixed). METHODS: Following >or= 6 consecutive weeks' stabilisation with open-label aripiprazole, patients were randomised (1 : 1) to aripiprazole or placebo. Patients completing 26 weeks treatment without relapse could continue for a further 74 weeks. Primary end-point was time to relapse for manic, mixed or depressive symptoms, defined as discontinuation due to lack of efficacy. Safety assessments included adverse event (AE) monitoring and changes in weight and lipid, glucose and prolactin levels. RESULTS: Of the 28 patients (aripiprazole, n = 14; placebo, n = 14) with rapid-cycling bipolar disorder, 12 (aripiprazole, n = 7; placebo, n = 5) completed the initial 26-week treatment period and three (all aripiprazole treated) completed the 100-week, double-blind period. Time to relapse was significantly longer with aripiprazole vs. placebo at week 26 [log-rank p = 0.033; 26-week hazard ratio = 0.21 (95% CI: 0.04, 1.03)] and week 100 [log-rank p = 0.017; 100-week hazard ratio = 0.18 (95% CI: 0.04, 0.88)]. The most commonly reported AEs with aripiprazole during the 100 weeks (>or= 10% incidence and twice placebo) were anxiety (n = 4), sinusitis (n = 4), depression (n = 3) and upper respiratory infection (n = 3). One aripiprazole-treated patient discontinued due to an AE (akathisia). There were no significant between-group differences in mean changes in weight or metabolic parameters. CONCLUSION: In this small, post hoc subanalysis, aripiprazole maintained efficacy and was generally well tolerated in the long-term treatment of rapid-cycling bipolar disorder. Further research with prospectively designed and adequately powered trials is warranted.

A single glycine residue at the entrance to the first membrane-spanning domain of the gamma-aminobutyric acid type A receptor beta(2) subunit affects allosteric sensitivity to GABA and anesthetics.

Site-directed mutagenesis of the gamma-aminobutyric acid type A (GABA(A)) receptor beta(2) subunit has demonstrated that conversion of a conserved glycine residue located at the entrance to the first transmembrane domain into the homologous rho(1) residue phenylalanine alters the modulating effects of four different i.v. anesthetics: pentobarbital, alphaxalone, etomidate, and propofol. Using the baculovirus expression system in Spodoptera frugiperda 9 cells, anesthetic-induced enhancement of [(3)H]muscimol and [(3)H]flunitrazepam binding in receptors containing the beta(2)(G219F) point mutation displayed a significantly reduced efficacy in modulation by all four i.v. anesthetics tested. Furthermore, GABA(A) receptors containing the alpha(1)(G223F) point mutation also significantly decreased the maximal effect of etomidate- and propofol-induced enhancement of ligand binding. Conversely, the homologous point mutation in rho(1) receptors (F261G) changed the i.v. anesthetic-insensitive receptor to confer anesthetic modulation of [(3)H]muscimol binding. Consistent with the binding, functional analysis of pentobarbital-enhanced GABA currents recorded with whole-cell patch clamp demonstrated the beta(2)(G219F) subunit mutation eliminated the potentiating effect of the anesthetic. Similarly, propofol-enhanced GABA currents were potentiated less in alpha(1)beta(2)(G219F)gamma(2) receptors than in alpha(1)beta(2)gamma(2) receptors. Although ligand binding displayed comparable K(D) values for muscimol among wild-type, alpha(1)beta(2)gamma(2), and mutant receptors, patch-clamp recordings showed that alpha(1)beta(2)(G219F)gamma(2) receptors had a significantly more potent response to GABA than did alpha(1)beta(2)gamma(2) or alpha(1)(G223F)beta(2)gamma(2). The alpha(1)beta(2)(G219F)gamma(2) receptors also were more sensitive to direct channel activation by pentobarbital and propofol in the absence of GABA. These results suggest that the first transmembrane glycine residue on the beta(2) subunit may be important for conformational or allosteric interactions of channel gating by both GABA and anesthetics.

Pharmacological and functional implications of developmentally-regulated changes in GABA(A) receptor subunit expression in the cerebellum.

The cerebellum undergoes many morphological, pharmacological, and electrophysiological changes during the first 3 weeks of postnatal development. The purpose of this review is to present the most up to date synopsis of the pharmacological and functional changes in, gamma-aminobutyric acid (GABA) type A receptors during this time of cerebellar maturation. Since most of the diversity in cerebellar, GABA(A) receptor pharmacology lies within the granule cell layer, research groups have focused on this area of the cerebellum to study the developmental changes in GABA(A) receptor subunit expression and the neurodifferentiating factors involved in regulating this expression. Thus, it is important to note that developmental changes in GABA(A) receptor composition and its corresponding pharmacology will be essential for determining the type of GABA-mediated transmission that occurs between neuronal contacts in the neonatal and subsequently in the mature cerebellum.

Expression of the GABA(A) receptor alpha6 subunit in cultured cerebellar granule cells is developmentally regulated by activation of GABA(A) receptors.

Primary cultures of cerebellar granule cells, prepared from cerebella of 7-day-old rats and cultured for 4 or 8 days, were used to study the neurodifferentiative effect of a GABA(A) receptor agonist, 4,5,6,7-tetrahydroisoxazol[5,4-c]pyridin-3-ol (THIP), on the expression of the alpha6 GABA(A) receptor subunit. Membranes prepared from these cultures were photolabeled with the imidazobenzodiazepine [3H]Ro15-4513. In THIP-treated cultures at 4 days in vitro (DIV), photolabeled [3H]Ro15-4513 binding in membranes was significantly increased for both the 51 kilodalton, kDa, (alpha1 subunit) and 56-kDa (alpha6 subunit) radioactive peaks in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In contrast, THIP-treated granule cells at 8 DIV demonstrated a small but significant decrease from control cultures in the photoincorporation of [3H]Ro15-4513 in the 51-kDa peak; however, no significant change in [3H]Ro15-4513 binding was observed for the 56-kDa polypeptide. Immunolabeling of the alpha6 subunit using silver-enhanced, immuno-gold staining of granule cells showed a significant effect with THIP treatment only at 4 DIV and not at 8 DIV. Examination by light microscopy demonstrated that the major effect of THIP was to increase alpha6 subunit clustering on granule cell bodies as well as neurites, 15-fold and sixfold, respectively. Using in situ hybridization, a small THIP-induced increase in alpha6 mRNA was detected at 4 DIV; however, no effect was apparent at 8 DIV. These data suggest that THIP has a trophic effect on alpha6 subunit expression, and this effect occurs only at an early developmental stage. Moreover, this study presents further evidence for the role of GABA(A) agonists, and thus the neurotransmitter, GABA, in regulating the expression of GABA(A) receptor subunits in the developing cerebellum.

Pentobarbital differentially enhances the affinity of [3H]flunitrazepam binding across brain regions.

The present study used saturation binding analyses to test the hypothesis that pentobarbital would differentially increase the affinity of benzodiazepine binding across brain regions. The results showed that there were significant (p < 0.05) regional differences in the dissociation constant (KD) for tritiated flunitrazepam ([3H]FLU) and that pentobarbital differentially decreased the KD for [3H]FLU across 6 brain regions. Pentobarbital caused the greatest decrease (-43%) in KD in the medulla. The results support the concept that type A gamma-aminobutyric acid (GABAA) receptor subtypes are localized differentially throughout the brain. Defining the regional specificity of interactions between benzodiazepines and barbiturates at the GABAA receptor will be important for understanding the mechanisms by which these drugs produce their behavioral effects in vivo.

Pharmacological characterization of muscarinic cholinergic receptors in cat pons and cortex. Preliminary study.

Muscarinic receptors (mAChRs) in the pontine reticular formation comprise a critical part of the REM sleep-generating system. Although the role of specific mAChR subtypes remains unclear, data from in vivo microinjection studies suggest that in the pons the M2 subtype is important for REM sleep generation. The present study tested the hypothesis that M2 antagonists would show a greater binding potency in feline pons than M1 or M3 antagonists. Competition binding assays showed 4-DAMP to be more potent than pirenzepine or AF-DX 116 in its ability to displace tritiated quinuclidinyl benzilate, and linear regression analyses indicated that 4-DAMP and pirenzepine each interacted with more than one binding site. These data demonstrate the presence of a mixture of mAChR subtypes in the feline pons, and are consistent with the view that REM sleep is mediated by more than one mAChR subtype.

Pentobarbital-enhanced [3H]flunitrazepam binding throughout the rat brain: an autoradiographic study.

The gamma-aminobutyric acidA/benzodiazepine receptor contains distinct ligand binding sites for hypnotic barbiturates and benzodiazepines. It is thought that barbiturate-induced sedation is produced, in part, by enhancing agonist binding to this receptor. The present study tested the hypothesis that pentobarbital would enhance benzodiazepine binding in a site-specific manner across the rat brain. In vitro receptor autoradiography was used to localize and quantitatively map [3H]flunitrazepam ([3H]FLU) binding in the absence and presence of pentobarbital in 133 brain areas. Each area demonstrated a statistically significant increase in [3H]FLU binding in the presence of in vitro pentobarbital (P < or = 0.05). Hindbrain nuclei dominated the top 20% of brain areas demonstrating the greatest pentobarbital-induced increases in [3H]FLU binding. The greatest mean percent increase in [3H]FLU binding occurred in the medulla, including areas known to be important for cardiovascular control, breathing, motor tone and regulating levels of arousal. These findings show that differential enhancement of benzodiazepine binding in the presence of pentobarbital occurred in brain areas controlling physiological functions known to be impaired by systemically administered pentobarbital.