Class Of Antipsychotic Agents Research Articles

Dopamine Receptor Partial Agonists for the Treatment of Bipolar Disorder.

Bipolar disorder is a chronic, disabling, and costly illness with frequent relapses and recurrences, high rates of co-morbid conditions, and poor adherence to treatment. Mood stabilizers and antipsychotics are the cornerstones of treatment. Dopamine receptor partial agonists are a novel class of antipsychotic agents with original pharmacodynamic properties. Among them, two have been approved by the US Food and Drug Administration for the treatment of bipolar disorder. Aripiprazole (oral formulation) has been approved as monotherapy for the treatment of manic/mixed episodes in adult and pediatric populations and for maintenance treatment in adults, and as adjunctive treatment to mood stabilizers, for the acute treatment of manic/mixed episodes and for maintenance in adults. An intramuscular formulation of aripiprazole has been approved for the treatment of agitation in mania and a long-acting injectable formulation has been approved as maintenance treatment. In the USA, cariprazine has been approved as monotherapy for the acute treatment of manic/mixed as well as bipolar depressive episodes. Brexpiprazole is not yet approved to treat bipolar disorder. The evidence supporting these indications is reviewed via an analysis of clinical registration trials as well as additional studies, on the basis of a systematic literature search. Further studies dealing with other aspects of bipolar illness are also presented. Aripiprazole and cariprazine are efficacious and generally well tolerated agents that have shown cost effectiveness, and may therefore enrich our therapeutic armamentarium for bipolar illness. Brexpiprazole, which displays an overall promising tolerability profile, deserves further efficacy studies.

Effects of agmatine on chlorpromazine toxicity in the liver of Wistar rats: the possible role of oxidant/antioxidant imbalance.

Chlorpromazine (CPZ) is a member of a widely used class of antipsychotic agents. The metabolic pathways of CPZ toxicity were examined by monitoring oxidative/nitrosative stress markers. The aim of the study was to investigate the hypothesis that agmatine (AGM) prevents oxidative stress in the liver of Wistar rats 48 h after administration of CPZ. All tested compounds were administered intraperitoneally (i.p.) in one single dose. The animals were divided into control (C, 0.9% saline solution), CPZ (CPZ, 38.7 mg/kg b.w.), CPZ+AGM (AGM, 75 mg/kg b.w. immediately after CPZ, 38.7 mg/kg b.w. i.p.), and AGM (AGM, 75 mg/kg b.w.) groups. Rats were sacrificed by decapitation 48 h after treatment. The CPZ and CPZ+AGM treatments significantly increased thiobarbituric acid reactive substances (TBARS), the nitrite and nitrate (NO2+NO3) concentration, and superoxide anion (O2•-) production in rat liver homogenates compared with C values. CPZ injection decreased the capacity of the antioxidant defense system: superoxide dismutase (SOD) activity, catalase (CAT) activity, total glutathione (GSH) content, glutathione peroxidase (GPx) activity, and glutathione reductase (GR) activity compared with the values of the C group. However, treatment with AGM increased antioxidant capacity in the rat liver; it increased the CAT activity, GSH concentration, GPx activity, and GR activity compared with the values of the CPZ rats. Immunohistochemical staining of ED1 in rats showed an increase in the number of positive cells 48 h after acute CPZ administration compared with the C group. Our results showed that AGM has no protective effects on parameters of oxidative and/or nitrosative stress in the liver but that it absolutely protective effects on the antioxidant defense system and restores the antioxidant capacity in liver tissue after administration of CPZ.

Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase

PDE10A is a recently identified phosphodiesterase that is highly expressed by the GABAergic medium spiny projection neurons of the mammalian striatum. Inhibition of PDE10A results in striatal activation and behavioral suppression, suggesting that PDE10A inhibitors represent a novel class of antipsychotic agents. In the present studies we further elucidate the localization of this enzyme in striatum of rat and cynomolgus monkey. We find by confocal microscopy that PDE10A-like immunoreactivity is excluded from each class of striatal interneuron. Thus, the enzyme is restricted to the medium spiny neurons. Subcellular fractionation indicates that PDE10A is primarily membrane bound. The protein is present in the synaptosomal fraction but is separated from the postsynaptic density upon solubilization with 0.4% Triton X-100. Immuno-electron microscopy of striatum confirms that PDE10A is most often associated with membranes in dendrites and spines. Immuno-gold particles are observed on the edge of the postsynaptic density but not within this structure. Our studies indicate that PDE10A is associated with post-synaptic membranes of the medium spiny neurons, suggesting that the specialized compartmentation of PDE10A enables the regulation of intracellular signaling from glutamatergic and dopaminergic inputs to these neurons.

Dopamine partial agonists: a new class of antipsychotic.

This review examines the development of dopamine partial agonists as a new class of antipsychotic agents. Partial agonists have a lower intrinsic activity at receptors than full agonists, allowing them to act either as a functional agonist or a functional antagonist, depending on the surrounding levels of naturally occurring neurotransmitter (full agonist). In the absence of a full agonist, partial agonists show functional agonist activity, binding to the receptor to produce a response. In the presence of a full agonist, partial agonists show functional antagonist activity, as receptor binding reduces the response from that seen with the full agonist. A partial agonist at dopamine D(2) receptors therefore offers an attractive option for the treatment of schizophrenia. It should act as a functional antagonist in the mesolimbic dopamine pathway, where excessive dopamine activity is thought to cause positive symptoms, but show functional agonist activity in the mesocortical pathway, where reduced dopamine activity is thought to be associated with negative symptoms and cognitive impairment. In addition, it should avoid the complete blockade of the nigrostriatal or tuberoinfundibular pathways, associated with extrapyramidal symptoms (EPS) and elevated prolactin levels, respectively. Clinical trials with aripiprazole - a new antipsychotic, which shows partial agonist activity at D(2) receptors and serotonin 5-HT(1A) receptors, and antagonist activity 5-HT(2A) receptors - have demonstrated the value of this treatment approach. Aripiprazole produced significant improvements in positive and negative symptoms in short- and long-term studies of patients with schizophrenia or schizoaffective disorder. Improvements occurred rapidly after the start of treatment, and were sustained throughout studies lasting up to 52 weeks. Significantly more patients responded to aripiprazole treatment than to haloperidol in the 52-week study, and aripiprazole-treated patients showed significantly greater improvements in negative and depressive symptoms than those receiving haloperidol. Aripiprazole treatment was well tolerated in both short- and long-term studies, showing a low liability for EPS and hyperprolactinemia, a lack of QTc prolongation, and minimal weight gain or sedation. In conclusion, the findings from clinical studies of aripiprazole show that dopamine partial agonists offer a novel, effective and well-tolerated treatment approach for patients with schizophrenia.

Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 1, "Goldilocks" actions at dopamine receptors.

Dopamine system stabilizers are a potential new class of antipsychotic agents without motor side effects. All known effective antipsychotics act at D2 receptors. A novel concept for an antipsychotic without motor side effects is to stabilize these receptors rather than block them harshly.

Acute quetiapine poisoning

Quetiapine (Seroquel®) is a member of a new class of antipsychotic agents used in the treatment of schizophrenia. Its pharmacologic effect is primarily mediated via antagonistic binding to serotonergic (5HT2) and dopaminergic (D2) receptors. Presented is a case of acute quetiapine overdose in a patient with associated tachycardia, hypotension, prolonged QTc, and rapid progression to coma. Management included activated charcoal, i.v. saline, and intubation for airway protection. The patient’s mental status rapidly improved within several hours of the ingestion, and the prolonged QTc and tachycardia resolved by the second and third days of hospitalization, respectively, without further intervention. This case illustrates the potential for hemodynamic instability and sudden deterioration in level of consciousness, warranting close monitoring and early intubation for airway protection. All patients with acute quetiapine overdose requiring hospitalization should be admitted to an intensive care unit setting.

Potential role of muscarinic receptors in schizophrenia

The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M 2 M 4 receptors and an antagonist at M 1, M 3 and M 5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice, d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.

Topographic EEG and receptor affinities of atypical neuroleptics

Quetiapine (Seroquel®) is a member of a new class of antipsychotic agents used in the treatment of schizophrenia. Its pharmacologic effect is primarily mediated via antagonistic binding to serotonergic (5HT2) and dopaminergic (D2) receptors. Presented is a case of acute quetiapine overdose in a patient with associated tachycardia, hypotension, prolonged QTc, and rapid progression to coma. Management included activated charcoal, i.v. saline, and intubation for airway protection. The patient’s mental status rapidly improved within several hours of the ingestion, and the prolonged QTc and tachycardia resolved by the second and third days of hospitalization, respectively, without further intervention. This case illustrates the potential for hemodynamic instability and sudden deterioration in level of consciousness, warranting close monitoring and early intubation for airway protection. All patients with acute quetiapine overdose requiring hospitalization should be admitted to an intensive care unit setting.

Visual working-memory dysfunction and P3 in schizophrenia

Quetiapine (Seroquel®) is a member of a new class of antipsychotic agents used in the treatment of schizophrenia. Its pharmacologic effect is primarily mediated via antagonistic binding to serotonergic (5HT2) and dopaminergic (D2) receptors. Presented is a case of acute quetiapine overdose in a patient with associated tachycardia, hypotension, prolonged QTc, and rapid progression to coma. Management included activated charcoal, i.v. saline, and intubation for airway protection. The patient’s mental status rapidly improved within several hours of the ingestion, and the prolonged QTc and tachycardia resolved by the second and third days of hospitalization, respectively, without further intervention. This case illustrates the potential for hemodynamic instability and sudden deterioration in level of consciousness, warranting close monitoring and early intubation for airway protection. All patients with acute quetiapine overdose requiring hospitalization should be admitted to an intensive care unit setting.

Risperidone: clinical issues in treatment.

On December 29, 1993, the Food And Drug Administration approved the new antipsychotic agent risperidone (Risperdal) for use in the United States. Risperidone is the first of a new class of antipsychotic agents known as serotonin/dopamine antagonists. It is only the second new antipsychotic medication to be introduced in this country during the past two decades. Early efficacy studies show that risperidone has marked superiority in reducing both positive and negative symptoms over placebos and haloperidol. Risperidone does not produce the blood dyscrasias associated with clozapine and possesses a relatively dean adverse reaction profile. Maximum therapeutic responses have been observed with doses of 4 mg to 8 mg; higher dosages have resulted in extrapyramidal symptoms without added benefits.