Efficacy Of Atypical Antipsychotic Drugs Research Articles

Pimavanserin augments the efficacy of atypical antipsychotic drugs in a mouse model of treatment-refractory negative symptoms of schizophrenia

Negative symptoms are a core, pervasive, and often treatment-refractory phenotype of schizophrenia, one which contributes to poor functional outcome, ability to work, pursue educational goals, and quality of life, as well as caretaker burden. Improvement of negative symptoms in some patients with schizophrenia has been reported with some atypical antipsychotic drugs [AAPDs], but improvement is absent in many patients and partial in others. Therefore, more effective treatments are needed, and better preclinical models of negative symptoms are needed to identify them. Sub-chronic [sc] treatment of rodents with phencyclidine [PCP], a noncompetitive N-methyl-d-aspartate [NMDAR] antagonist, produces deficits in social interactions [SI] that have been widely studied as a model of negative symptoms in schizophrenia. Acute restraint stress [ARS] also provides a model of treatment-refractory negative symptoms [TRS] to AAPDs. By themselves, in sc-PCP mice, the AAPDs, risperidone, olanzapine, and aripiprazole, but not the selective 5-HT2AR inverse agonist, pimavanserin [PIM], rescued the SI deficit in sc-PCP mice, as did the combination of PIM with sub-effective doses of each of these AAPDs. These three AAPDs alone did not rescue SI deficit in sc-PCP+ 2 h-ARS mice, indicating these mice were treatment refractory. However, co-administration of PIM with any of the AAPDs significantly restored SI in these mice. PIM may be an effective adjunctive therapy for treating negative symptoms of schizophrenia in some patients who have failed to respond to AAPDs, but further studies are needed.

S247. Therapeutic Efficacy of Atypical Antipsychotic Drugs by Targeting Multiple Stress-Related Metabolic Pathways in Schizophrenia Patients

S247. Therapeutic Efficacy of Atypical Antipsychotic Drugs by Targeting Multiple Stress-Related Metabolic Pathways in Schizophrenia Patients

Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways

Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic–pituitary–adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography–mass spectrometry (UPLC–MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine–phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment.

Blockade of MK-801-Induced Heat Shock Protein 72/73 in Rat Brain by Antipsychotic and Monoaminergic Agents Targeting D2, 5-HT<sub>1A</sub>, 5-HT<sub>2A</sub> and α<sub>1</sub>-Adrenergic Receptors

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can produce positive and negative symptomatology as well as impairment of cognitive function that closely resemble those present in schizophrenia. In rats, these drugs induce a behavioral syndrome (characterized by hyperlocomotion and stereotypies), an enhanced glutamatergic transmission in the medial prefrontal cortex, and damage to retrosplenial cortical neurons in adult rats, which was measured as the induction of the stress protein 72/73 kDa heat shock protein (Hsp72/73). In the present work, we have examined the existence of possible differences among different antipsychotic drugs in their capacity to block immunolabeling of Hsp72/73 in the retrosplenial cortex of the rat induced by the potent NMDA receptor antagonist, MK- 801. In addition, the effects of selective monoaminergic agents were also studied to delineate the particular receptors responsible for the actions of antipsychotic drugs. Pretreatment with clozapine, chlorpromazine, olanzapine, ziprasidone--and to a lesser extent haloperidol-reduced the formation of Hsp72/73 protein in the rat retrosplenial cortex after the administration of MK-801. In addition, antagonism at dopamine D2 (raclopride), 5-HT2 (M100907) and α1- adrenoceptors (prazosin) as well as agonism at 5-HT1A receptors (BAY x 3702) also diminished the MK-801-induced number of cells labeled with Hsp72/73. Each of these effects may contribute to antipsychotic action. The results suggest that the efficacy of atypical antipsychotic drugs in the clinic may result from a combined effect on 5-HT2, 5-HT1A and α1-adrenergic receptors added to the classical dopamine D2 receptor antagonism.

5-HT1A Receptor Agonists Enhance Pyramidal Cell Firing in Prefrontal Cortex Through a Preferential Action on GABA Interneurons

5-HT(1A) receptors (5-HT1AR) are expressed by pyramidal and γ-aminobutyric acidergic (GABAergic) neurons in medial prefrontal cortex (mPFC). Endogenous serotonin inhibits mPFC pyramidal neurons via 5-HT1AR while 5-HT1AR agonists, given systemically, paradoxically excite ventral tegmental area-projecting pyramidal neurons. This enhances mesocortical dopamine function, a process involved in the superior efficacy of atypical antipsychotic drugs on negative and cognitive symptoms of schizophrenia. Moreover, the 5-HT1AR-induced increase of pyramidal discharge may also contribute to the maintenance of activity patterns required for working memory, impaired in schizophrenia. Given the importance of these processes, we examined the neurobiological basis of pyramidal activation through 5-HT1AR using the prototypical agent 8-OH-DPAT. (±)8-OH-DPAT (7.5 μg/kg i.v.) increased discharge rate and c-fos expression in rat mPFC pyramidal neurons. Local blockade of GABA(A) inputs with gabazine (SR-95531) avoided (±)8-OH-DPAT-induced excitations of pyramidal neurons. Moreover, (±)8-OH-DPAT administration reduced the discharge rate of mPFC fast-spiking GABAergic interneurons at doses exciting pyramidal neurons. Activation of other 5-HT1AR subpopulations (raphe nuclei or hippocampus) does not appear to contribute to pyramidal excitations. Overall, the present data suggest a preferential action of (±)8-OH-DPAT on 5-HT1AR in GABAergic interneurons. This results in pyramidal disinhibition and subsequent downstream excitations of subcortical structures reciprocally connected with PFC, such as midbrain dopaminergic neurons.

Memory Walk Steps Up AD Cause

Memory Walk Steps Up AD Cause

Efficacy of atypical antipsychotic drugs for delusions in schizophrenia spectrum disorders

aYahagigawa Hospital, Aichi, Japan bShukutoku University, Aichi, Japan cNational Institute of Neuroscience, Tokyo, Japan 15th Annual Meeting of the Japanese Society of Clinical Neuropsychopharmacology, Tokyo, Japan, 11–13 October 2005

Presynaptic dopamine D(4) receptor localization in the rat nucleus accumbens shell.

Dopamine D(4) receptors in the nucleus accumbens shell (AcbSh) are thought to play a key role in mediating the locomotor and sensitizing affects of psychostimulants, as well as the therapeutic efficacy of atypical antipsychotic drugs. We used electron microscopic immunocytochemistry to determine the functional sites for endogenous and exogenous D(4) receptor activation in this region. Of 1,090 D(4) receptor-labeled profiles observed in the AcbSh of rat brain, 65% were axons and axon terminals, while 22% were dendrites and dendritic spines. Within axons and terminals, D(4) receptor immunoreactivity was localized to segments of the plasma membrane and membranes of nearby vesicles. The axon terminals were morphologically heterogenous, varying in size and content of either all small synaptic vesicles (ssv), or ssv and large dense-core vesicles. The labeled terminals occasionally formed asymmetric excitatory-type axospinous synapses, but the majority were without recognizable synaptic specializations. In a separate series of tissue sections that were processed for dual-labeling of the D(4) receptor and the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), 56% of all observed associations were appositions between differentially labeled axonal profiles, and 17% were terminals that contained immunoreactivity for both antigens. Dendritic spines containing D(4) receptor-labeling also received convergent input from TH-immunoreactive terminals and unlabeled terminals forming asymmetric synapses. These results provide the first ultrastructural evidence for a major presynaptic, and a more minor postsynaptic, involvement of D(4) receptors in dopaminergic modulation of excitatory transmission in the AcbSh.