Psychosocial functioning in patients with schizophrenia treated with aripiprazole - an office-based real-world setting. Results from the German post-marketing surveillance study.

AIM: Aripiprazole (ABILIFY) is an effective antipsychotic used in a dose range from 10 to 30 mg, administered once daily. Soon after its approval in Germany for treatment of schizophrenia, a 12-month post-marketing surveillance study was initiated that included 1 096 patients cared for by 408 office-based psychiatrists and/or neurologists in private practice. The aim was to gain further insights into safety and efficacy of aripiprazole in an outpatient real-life setting focusing on general health, well-being and psychosocial functioning. PATIENTS AND METHODS: Efficacy was rated by using standard CGI, SF-12 and SIWM-PsySo instruments for severity of disease, physical and mental health outcomes and psychosocial state, respectively. Safety was evaluated according to the reports of adverse events. Mean total daily dose of aripiprazole increased from 15.4 mg at the visit after 1 month to 17.6 mg at the visits after 6 to 12 months, the most frequently administered maintenance dose being 15 mg. RESULTS AND DISCUSSION: Within the observation period significant improvements of CGI, SF-12 and SIWM-PsySo scores over time versus baseline values were observed (p<0.001) when starting with or switching to aripiprazole. Physicians observed improvements in 80.7% of the patients at endpoint; in 62% of the patients the disease state was considered "much" or "very much" improved. Aripiprazole was overall well tolerated; 19.9% of patients discontinued treatment after 12 months. Adverse effects in general were moderate to mild and corresponded to the known tolerability profile of aripiprazole. Psychotic side effects reported were probably due to a recurrence of the underlying schizophrenic disorder. CONCLUSION: The results indicate that aripiprazole may be an efficacious and safe treatment option for pre-treated patients with schizophrenia also in a naturalistic psychiatrist/neurologist practice setting with effects on health and psychosocial functioning and a comparably low dropout rate.

Aripiprazole: pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia.

Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at Dopamin D2- and Serotonin-5-HT1A-receptors as well as an antagonism at Serotonin-5-HT2A-receptors. Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability. The special pharmacodynamics of aripiprazole are described herein.

Glutamate-induced Co2+ uptake in rat auditory brainstem neurons reveals developmental changes in Ca2+ permeability of glutamate receptors.

Ca2+ influx through glutamate receptors (GluRs) is thought to play a crucial part in developmental processes and neuronal plasticity. Here we have examined the spatiotemporal distribution of Ca2+-permeable GluRs in auditory brainstem neurons of the rat from birth to adulthood, using the cobalt-staining technique of Pruss and collaborators. In slices of young adult rats, 1 mM glutamate evoked intense cobalt uptake in subsets of neurons in the ventral cochlear nuclei, the medial nucleus of the trapezoid body, the lateral and the medial superior olive, and the lateral lemniscal nuclei. Neurones in the central nucleus of the inferior colliculus, and thalamic auditory nuclei appear to express few, if any, Ca2+-permeable GluRs. Thus, in adults, Ca2+-permeable GluRs are present in neurons of almost all main relay stations of the auditory brainstem. During development, cobalt-stained cells first appeared at about hearing onset (at postnatal day 12 [P12]). At P16, staining levels were highest and the pattern of distribution was already adult-like. The staining intensity slightly declined during the fourth postnatal week. In contrast, Ca2+-permeable receptors were detected in the external cortex of the inferior colliculus as early as P4. Our results show that auditory neurons, characterized by a high temporal precision in neuronal activity, display Ca2+-permeable GluRs. Because Ca2+ permeability appears at about the onset of hearing and is highest during the following 2 weeks, Ca2+ influx through GluRs is likely to be implicated in remodelling processes occurring during this ontogenetic period.

Electrical membrane properties of trapezoid body neurons in the rat auditory brain stem are preserved in organotypic slice cultures.

The medial nucleus of the trapezoid body (MNTB) is a conspicuous structure in the mammalian auditory brain stem. It is a major component of the superior olivary complex and is involved in sound localization. Recently, organotypic slice culture preparations of the superior olivary complex were introduced to investigate the development of inhibitory and excitatory projections (Sanes and Hafidi, 1996; Lohmann et al., 1998). In the present article, we further assessed the organotypicity of our culture system (Lohmann et al., 1998) and examined electrical membrane properties of MNTB neurons expressed under culture conditions. To do so, MNTB neurons from early postnatal rats (P3-5) were studied after 3-6 days in vitro (DIV) by whole-cell patch-clamp recordings. Their mean resting potential was -59 mV, the input resistance averaged 171 Momega, and the average time constant was 3 ms. Four types of voltage-activated conductances were observed in voltage-clamp recordings. All cells expressed a tetrodotoxin (TTX)-sensitive sodium current. Two types of potassium currents could be characterized: a tetraethylammonium (TEA) -sensitive and a 4-aminopyridine (4-AP)-sensitive conductance, both of which are composed of a transient and a sustained component. Finally, an inwardly rectifying current, activated by hyperpolarizing voltage steps, was found. In current-clamp recordings, depolarizing current pulses typically elicited a single action potential. In the presence of 4-AP, however, these current pulses induced a train of action potentials. The duration of action potentials was increased by 4-AP and the afterhyperpolarization was reduced. Hyperpolarizing current injections induced a "sag" in the membrane potential, indicating the influence of an inwardly rectifying current. Our results demonstrate that MNTB neurons in slice cultures have electrical membrane properties comparable to those of their counterparts in acute slices.

Physiology and pharmacology of native glycine receptors in developing rat auditory brainstem neurons.

Glycinergic neurotransmission is mediated via inhibitory glycine receptors (GlyRs) which are heterogeneous during development. Electrophysiological studies performed on recombinant GlyRs have identified different pharmacological properties and attributed them to differences in their subunit composition. Here, we report on age-related changes in the response properties of native GlyRs in the mammalian brain. Whole-cell patch-clamp recordings were obtained from neurons of the medial nucleus of the trapezoid body (MNTB), a major relay station in the mammalian auditory brainstem. Experiments were performed in acute medullary slices of rats between postnatal day (P) 1 and P15, a period during which synapse maturation occurs. Glycine-induced currents were present throughout the period under investigation and displayed age-related modifications in their amplitude, kinetic characteristics, and sensitivity to drugs. Current amplitudes and GlyR desensitization behavior increased with age. The alpha 1 subunit-specific GlyR antagonist cyanotriphenylborate (CTB) was barely effective in reducing glycine-induced currents during the first few postnatal days, yet a significant increase of the inhibitory effect occurred after the first postnatal week. This finding indicates that alpha 1 subunit-containing GlyRs become expressed only postnatally in the MNTB. Picrotoxin, which most effectively blocks recombinant alpha 2-homooligomers, reduced glycine-induced currents in neonatal MNTB neurons, suggesting that alpha 2-homooligomers may form native GlyR isoforms. Our results show that the physiology and pharmacology of GlyRs in the auditory brainstem underlie age-related changes which are most probably produced through a replacement of "neonatal" alpha 2 subunits with "adult" alpha 1 subunits.

Influence of the neuropeptide somatostatin on the development of dendritic morphology: a cysteamine-depletion study in the rat auditory brainstem.

We investigated the functional role of somatostatin during early ontogeny of the brain, when the neuropeptide as well as its receptors are heavily expressed in the auditory brainstem. Rat pups received a daily injection of cysteamine which, when applied at low concentrations, most selectively depletes somatostatin. Neurons from the lateral superior olive, an auditory brainstem nucleus which transiently receives a dense somatostatinergic input, were intracellularly labeled at postnatal day 14 or 18. The dendritic morphology of these neurons was then analyzed quantitatively and compared with neurons from controls. Cysteamine treatment induced a reduction of the number of dendritic end points by more than 50%. At postnatal day 14, for example, controls and somatostatin-depleted animals had an average of 58 and 28 end points, respectively. The number of primary dendrites was also significantly reduced by cysteamine. In contrast, the size of the somata, the orientation of the dendritic trees within the lateral superior olive, the dendritic areas, and the cross-sectional size of the lateral superior olive were not altered. These results indicate that somatostatin depletion during early development has profound effects on the maturation of dendritic morphology. The selective influence on the dendritic trees suggests that somatostatin acts as an endogenous trophic peptide and promotes the achievement of dendritic complexity.

Presence of somatostatin sst2 receptors in the developing rat auditory system.

A transient expression of somatostatin mRNA as well as of the peptide itself has been described in the developing mammalian auditory brainstem. However, little is known about the presence, and the spatial and temporal pattern of somatostatin (SRIF) receptor subtypes in this system. Therefore, we investigated the distribution of SRIF receptor binding sites labeled with the radioligands [125I]LTT-SRIF-28, [125I]Tyr3-octreotide, and [125I]CGP 23996 (in buffers containing either Mg2+ or Na+ ions) within the developing auditory brainstem of the rat. In addition, we performed in situ hybridization with a 35P-labeled oligoprobe, specific for somatostatin sst2 receptor mRNA. We observed a transient expression of SRIF receptors, labeled with [125I]LTT-SRIF-28, [125I]Try3-octreotide, and [125I]CGP 23996 (only in the presence of Mg2+ ions), in all principal auditory nuclei during neonatal development. In the adult rats, however, only the inferior colliculus displayed significant SRIF receptor binding. A very similar spatiotemporal labeling pattern was found for sst2 receptor mRNA. Our in situ hybridization data, together with those on ligand binding, suggest a predominantly transient expression of sst2 receptors in the auditory system. Since sst2 sites (and possibly sst3 and sst5) as well as SRIF itself appear to be co-expressed during a period when synapse maturation occurs, we suggest that sst2 receptors are involved in this process of the developing auditory system.

Cysteamine impairs the development of the acoustic startle response in rats: possible role of somatostatin.

Somatostatin is transiently expressed in many regions of the developing brain, among others in auditory brainstem nuclei of neonatal rats. To explore the functional significance of somatostatin during the ontogeny of acoustically elicited behavior, the acoustic startle response (ASR) was measured in developing rats after chronic application of cysteamine, which, when applied in low doses, most selectively depletes somatostatin. Cysteamine treatment drastically reduced somatostatin immunoreactivity in the cochlear nuclear complex and the caudal pontine reticular nucleus, i.e. in structures mediating the ASR. It did not affect the ASR amplitude of postnatal day (P) 13 animals, yet it resulted in a significant reduction of the ASR amplitude at P18. Our results therefore suggest that somatostatin can influence the maturation of sensorimotor information processing.

Cholecystokinin enhances the acoustic startle response in rats.

The present study examined the effects of the neuropeptide cholecystokinin (CCK) on neurones of the caudal pontine reticular nucleus (PnC), which mediates the acoustic startle response (ASR) in rats. Electrophysiological experiments revealed an excitatory effect of CCK on acoustically responsive neurones in the PnC. On the behavioural level, CCK also enhanced the ASR. Since the PnC is not only an obligatory relay station of the brain circuit mediating the ASR, but also receives modulatory input from brain areas involved in the expression of fear and anxiety, the enhancement of the ASR by CCK could be interpreted as an anxiogenic-like effect of this peptide.

Somatostatin and leu-enkephalin in the rat auditory brainstem during fetal and postnatal development.

A transient expression of the neuropeptide somatostatin has been described in several brain areas during early ontogeny and several opioid peptides, such as leu-enkephalin, have also been found in the brain at this stage in development. It is therefore believed that somatostatin and leu-enkephalin may play a role in neural maturation. The aim of the present study was to describe the spatiotemporal pattern of somatostatin and leu-enkephalin immunoreactivity in the auditory brainstem nuclei of the developing rat and to correlate it with other developmental events. In order to achieve this goal, we applied peroxidase-antiperoxidase immunocytochemistry to rat brains between embryonic day (E) 17 and adulthood. Somatostatin immunoreactivity (SIR) was found in all nuclei of the auditory brainstem, yet it was temporally restricted in most nuclei. SIR appeared prenatally and reached maximum levels around postnatal day (P) 7, when great numbers of immunoreactive neurons were present in the ventral cochlear nucleus (VCN) and in the lateral lemniscus. At that time relatively low numbers of cells were labeled in the dorsal cochlear nucleus, the lateral superior olive (LSO), and the inferior colliculus (IC). During the same period, when somata in the VCN were somatostatin-immunoreactive (SIR), a dense network of labeled fibers was also present in the LSO, the medial superior olive (MSO), and the medial nucleus of the trapezoid body (MNTB). As these nuclei receive direct input from VCN neurons, and as the distribution and morphology of the somatostatinergic fibers in the superior olivary complex (SOC) was like that of axons from VCN neurons, these findings suggest a transient somatostatinergic connection within the auditory system. Aside from the LSO, MSO, and MNTB, labeled fibers were found to a smaller extent in all other auditory brainstem nuclei. After P7, the SIR decreased and only a few immunoreactive elements were found in the adult auditory brainstem nuclei, indicating that somatostatin is transiently expressed in the rat auditory brainstem. Leu-enkephalin immunoreactivity showed a lower number and weaker intensity of labeled structures as compared to SIR, with E18 being the earliest day at which labeled fibers appeared in the SOC. At birth, immunoreactive fibers were also present in the cochlear nuclear complex and in the IC. Leu-enkephalin immunoreactive somata were found only after P12 in the CN and after P16 in the IC. Leu-enkephalin immunoreactivity was not transient, but increased progressively with age until about P21, when the adult levels were reached.(ABSTRACT TRUNCATED AT 400 WORDS)

Substance P and other putative transmitters modulate the activity of reticular pontine neurons: an electrophysiological and immunohistochemical study.

In this study we investigated the effects of possible modulatory transmitters on acoustically responsive neurons of the caudal pontine reticular nucleus (PnC). From previous work in our laboratory it has been suggested that the acoustically responsive giant neurons of this nucleus are the sensorimotor interface mediating the acoustic startle response. Furthermore they are the site of some of the modulatory influence impinging on this response. Besides a possibly glutamatergic excitation from the amygdala a cholinergic input from the midbrain has been described which may use substance P as cotransmitter. Therefore we used electrophysiological and histochemical methods to study this possible modulatory influence in the caudal pontine reticular nucleus. In the first part of this study we recorded extracellularly from single units in the PnC in vivo and studied the effects of iontophoretically applied transmitters. Substance P elicited a long lasting excitation. This excitatory effect of SP was potentiated by acetyl-beta-methylcholine (AMCh, an acetylcholine agonist), whereas single application of AMCh showed no uniform response. Glutamate elicited a potent brief excitation, while application of GABA showed a potent brief inhibition of PnC neurons. In the second part of this study we employed immunoperoxidase staining for substance P, which revealed a fairly dense network of substance P-immunoreactive (SP-ir) fibers in the lateral and ventral aspects of the PnC. Combining retrograde tracing and immunocytochemistry for substance P, we demonstrated that the SP-ir axons in the PnC originate mainly in the laterodorsal tegmental nucleus. We therefore conclude that activation of the laterodorsal tegmental nucleus may facilitate the acoustic startle response by a long lasting excitation of neurons in the caudal pontine reticular nucleus.

Cholinergic neurons in the pedunculopontine tegmental nucleus are involved in the mediation of prepulse inhibition of the acoustic startle response in the rat.

The amplitude of the acoustic startle response (ASR) is markedly reduced when the startle eliciting pulse is preceded by a weak, non-startling stimulus at an appropriate lead time, usually about 100 ms. This phenomenon is termed prepulse inhibition (PPI) and has received considerable attention in recent years as a model of sensorimotor gating. We report here on experiments which were undertaken in order to investigate some of the neural mechanisms of PPI. We focused on the characterization of the cholinergic innervation of the pontine reticular nucleus, caudal part (PnC), an obligatory relay station in the primary startle pathway. The combination of retrograde tracing with choline acetyltransferase-immunocytochemistry revealed a cholinergic projection from the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDTg) to the PnC. Extracellular recording from single PnC units, combined with microiontophoretic application of the acetylcholine (ACh) agonists acetyl-beta-methylcholine (AMCH) and carbachol revealed that ACh inhibits the majority of acoustically responsive PnC neurons. Neurotoxic lesions of the cholinergic neurons of the PPTg significantly reduced PPI without affecting the ASR amplitude in the absence of prepulses. No effect on long-term habituation of the ASR was observed. The present data indicate that the pathway mediating PPI impinges upon the primary acoustic startle circuit through an inhibitory cholinergic projection from the PPTg to the PnC.