Class Of Atypical Antipsychotics Research Articles

Do We Need a New Nomenclature for Atypical Antipsychotics? A Survey of Health Care Professionals and Patients.

Objective: The current nomenclature for atypical antipsychotics does not indicate that they are used to treat nonpsychotic conditions (eg, bipolar disorder, major depressive disorder), which could have negative implications for both health care providers (HCPs) and patients. The objective of this study was to evaluate how the atypical antipsychotic class name affects HCPs who treat bipolar disorder and patients who receive the diagnosis. Methods: Nationwide surveys of primary care and psychiatric HCPs (n = 200) and patients with bipolar disorder (n = 200) were conducted to assess perspectives regarding current atypical antipsychotic nomenclature. HCP opinion about a change in class name was also evaluated. The self-administered electronic surveys were completed by HCPs from May 22, 2020, to June 1, 2020, and by patients from August 25, 2020, to September 7, 2020. Results: Compared with the mood stabilizer class name, the atypical antipsychotic name elicited stronger negative feelings from both HCPs and patients. Most HCPs avoided bringing up the atypical antipsychotic name with patients (72%), often due to fear of negative reactions. Despite being approved for bipolar mania and depression, only 48% and 39% of HCPs indicated that atypical antipsychotics were appropriate for these disorders, respectively. If an appropriate alternative for the term atypical antipsychotic was available for bipolar disorder, 71% of HCPs said they were likely to change their class-related behaviors. Most patients had never heard of the atypical antipsychotic class name (69%). Significantly more patients had negative reactions (eg, worry, fear, confusion) to the idea of their HCP prescribing an atypical antipsychotic versus a mood stabilizer (25% vs 6%). Compared with mood stabilizers, patients were less likely to take an atypical antipsychotic immediately as prescribed. Conclusions: Significantly more HCPs and patients had negative reactions to atypical antipsychotic nomenclature compared with mood stabilizer nomenclature for treating bipolar disorder. The broad descriptive atypical antipsychotic class name may not support the standard of care for the treatment of bipolar disorder.

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics.

Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects.

Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences.

The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in symptoms severity, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D2 receptor antagonists and they act beyond D2 antagonism, involving other receptor targets which regulate dopamine and other neurotransmitters. Consequently, AAPs present a significant reduction of deleterious side effects like parkinsonism, hyperprolactinemia, apathy and anhedonia, which are all linked to the strong blockade of D2 receptors. This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them. Furthermore, we propose a continuum spectrum of "atypia" that begins with risperidone (the least atypical) to clozapine (the most atypical), while all the other AAPs fall within the extremes of this spectrum. Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses present in Parkinson's disease, though it has been associated with adverse effects like agranulocytosis (0.7%) and weight gain, pushing the scientific community to find new drugs as effective as clozapine, but devoid of its side effects. To achieve this, it is therefore imperative to characterize and compare in depth the very complex molecular profile of AAPs. We also introduce relatively new concepts like biased agonism, receptor dimerization and neurogenesis to identify better the old and new hallmarks of "atypia". Finally, a detailed confrontation of clinical differences among the AAPs is presented, especially in relation to their molecular targets, and new means like therapeutic drug monitoring are also proposed to improve the effectiveness of AAPs in clinical practice.

Schizophrenia drug discovery and development in an evolving era: are new drug targets fulfilling expectations?

Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.

A Murine Model of Atypical Antipsychotic‐Induced Weight Gain and Metabolic Dysregulation

In comparison with conventional, first-generation antipsychotics (e.g., haloperidol), the administration of atypical antipsychotics (AAPs) has been associated with a higher risk of metabolic derangements, including body weight increase, dysregulation of glucose homeostasis, fat accumulation, and even liability to develop type II diabetes. Since this is a serious clinical problem that may be further exacerbated in overweight schizophrenics, establishing animal models of AAP-induced adverse effects may contribute to clarifying the mechanisms underlying these effects. Here we present three basic protocols by which this problem has been modeled. The three protocols differ in many aspects (routes of administration, extent of the chronic treatment, diets, and dosage regimen), and the pros and cons of each procedure are systematically detailed throughout. It should be noted that several factors (e.g., species, sex, duration, and class of AAPs) could restrict the feasibility of these models, as well as their correspondence to the clinical condition.

Aripiprazole-Induced Parkinsonism and Its Association With Dopamine and Serotonin Receptor Polymorphisms

To the Editors:Aripiprazole (ARI), the first of a new class of atypical antipsychotics approved for treatment of schizophrenia, functions as a partial dopaminergic agonist, acting on both postsynaptic D2 receptors and presynaptic autoreceptors. In addition, ARI displays partial agonism at serotonin

Aripiprazole in the Treatment of Depressive and Anxiety Disorders

Despite the availability of different classes of drugs for the treatment of depressive and anxiety disorders, there are a number of clinically significant unmet needs, such as a high prevalence of treatment resistance, partial response, subsyndromal symptomatology, recurrence and relapse. With the approval of atypical antipsychotics, which are associated with a lower adverse effect burden than typical antipsychotics, consideration of their off-label use for the treatment of affective disorders and various other psychiatric disorders has become a viable option. However, consideration should be given to the US FDA black box warning indicating that atypical antipsychotics may increase mortality risk, particularly in the elderly population with dementia-related psychosis. There has been much conjecture about the utility of these atypical drugs to facilitate traditional antidepressant therapy, either in combination (from the initiation of therapy) or as adjunctive therapy (in the case of partial/incomplete response). Nevertheless, at present, available evidence from randomized, placebo-controlled trials is sparse, and a formal risk/benefit assessment of the use of these agents in a nonpsychotic patient population is not yet possible. As a representative agent from the atypical antipsychotic class with a novel mechanism of action and a relatively low adverse effect burden, aripiprazole represents an interesting potential treatment for depressive and anxiety disorders. In this review, we focus on the rationale for the use of aripiprazole in these disorders. Preclinical data suggests that aripiprazole has a number of possible mechanisms of action that may be important in the treatment of depressive and anxiety disorders. Such mechanisms include aripiprazole action at serotonin (5-HT) receptors as a 5-HT1A partial receptor agonist, a 5-HT2C partial receptor agonist and a 5-HT2A receptor antagonist. Aripiprazole also acts as a dopamine D2 partial receptor agonist, and has a possible action at adrenergic receptors. Furthermore, aripiprazole may have possible neuroprotective effects. Clinical studies demonstrate that aripiprazole may be useful in the treatment of bipolar depression, major depressive disorder, treatment-resistant depression and possibly anxiety disorders. Clinical data also suggest that aripiprazole may have a lower adverse effect burden than the other atypical drugs. Future research may confirm the potential utility of aripiprazole in the treatment of depressive and anxiety disorders.

Aripiprazole as the Causative Agent of Neuroleptic Malignant Syndrome

Aripiprazole as the Causative Agent of Neuroleptic Malignant Syndrome

Differential trends in prevalence of diabetes and unrelated general medical illness for schizophrenia patients before and after the atypical antipsychotic era

Objective To estimate the net growth in the risk of type 2 diabetes mellitus (DM) in the population of patients with schizophrenia that may be attributable to the increased use of the class of atypical antipsychotics (A-APDs), adjusting for community trends in DM risk. Methods Using data from the National Hospital Discharge Survey, we perform trend analyses for prevalence of DM and general illness unrelated to insulin resistance in patients with schizophrenia, as well as in individuals without known mental illness, during three time periods: 1) prior to any A-APDs introduction (1979–1989); 2) short-term after their introduction (1990–1995), and long-term following their introduction (1996–2001). Results Trends in DM and general illness risks were comparable among inpatients with schizophrenia and those without mental illness during the pre-A-APD era and the short-term post-A-APDs era. During 1996–2001, the net difference in DM prevalence grew at an increasing rate (0.7% per year, p < 0.001). By 2001, over a base DM prevalence of 10% in patients with schizophrenia, 3.1 percentage points ( p = 0.016) could be attributed to the use of A-APDs. There was no significant net growth in the prevalence of general illness during this period for these patients. This growth was most pronounced among African-American females and middle aged (35–49 years old) patients. This increased risk of DM translates into additional direct medical costs of $800 million per year. Conclusions The introduction of A-APDs, after a lag period, is associated with increased risk of DM. This needs to be considered in light of the advantages of these drugs in efficacy and tolerability. Long-term studies are necessary to identify the effect of individual A-APDs on DM risk.

Aripiprazole (Abilify™) Overdose in a Child

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butyloxy}-3,4-dihydro-2(1H)-quinolinone, is an atypical antipsychotic medication inaugurating the newest class of atypical antipsychotics: the partial dopamine agonists. It has a particularly long half-life of elimination and variable metabolism secondary to genetic polymorphism. We report an unintentional overdose of 195 mg (17.1 mg/kg) of aripiprazole in a 2.5 year-old child. This patient exhibited CNS depression not requiring respiratory support and without significant cardiovascular effects. CNS effects persisted for almost 2 weeks postingestion.

Current Options in the Management of Olanzapine-Associated Weight Gain

To evaluate options for the management of weight gain associated with olanzapine therapy. MEDLINE (1966-May 2004), International Pharmaceutical Abstracts (1970-August 2003), The Cochrane Library, and EMBASE (1974-August 2003) databases were searched using the key words antipsychotics, atypical antipsychotics, olanzapine, and weight gain. Bibliographies of cited articles were reviewed. All articles identified from the data sources were evaluated and all information deemed relevant was included for this review. Weight gain is a common adverse effect of olanzapine, a member of the atypical antipsychotic class. Data are limited supporting a specific therapeutic approach to the management of weight gain with olanzapine treatment. Reversal of weight gain with lifestyle modifications and adjunctive pharmacologic therapies such as nizatidine and amantadine has been modest. Experience with adjunctive pharmacologic treatment has been limited to small, observational studies and case reports. Although data are limited, weight reduction has been observed in select patients switching from olanzapine to an alternative atypical antipsychotic. At this time, targeting lifestyle modifications provides the most reasonable approach to minimize weight gain observed with olanzapine therapy. Preliminary evidence evaluating adjunctive pharmacologic treatment for this indication has demonstrated minimal clinical benefit. Switching to an alternative atypical antipsychotic agent associated with less significant weight gain may be appropriate in select patients. Further clinical trials are needed to support a specific therapeutic approach to managing weight gain with olanzapine.

Aripiprazole (Abilify™) Overdose in a Child

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butyloxy}-3,4-dihydro-2(1H)-quinolinone, is an atypical antipsychotic medication inaugurating the newest class of atypical antipsychotics: the partial dopamine agonist. It has a particularly long half-life of elimination and variable metabolism secondary to genetic polymorphism. We report an unintentional overdose of 195 mg (17.1 mg/kg) of aripiprazole in a 2.5 year-old child. This patient exhibited CNS depression not requiring respiratory support and without significant cardiovascular effects. CNS effects persisted for almost 2 weeks postingestion.

Pharmacokinetic Profile and Clinical Efficacy of Long-Acting Risperidone

Continuous long-term antipsychotic therapy is required for patients with schizophrenia to optimise treatment benefits. The use of long-acting antipsychotic preparations can help to ensure compliance with therapy and has been shown to improve efficacy in relapse prevention when compared with oral agents. How- ever, the use of long-acting agents has been limited, since this approach to patient care has only been available with conventional drugs. The atypical antipsychotic agents have provided a new option for the treatment of schizophrenia. However, entwined with health system limitations, partial or non-compliance remains a problem with oral atypical antipsychotic agents. Combining the attributes of the atypical antipsychotic class with the pharmacokinetic profile and compliance advantages of a long-acting formulation could potentially be an important advance in the management of patients requiring continuous anti- psychotic therapy. This review considers the available clinical data supporting possible advantages for the only long-acting atypical agent currently available, long-acting risperidone, as a microsphere formulation. The drug-delivery technology employed provides a sustained therapeutic plasma level, with administration once every 2 weeks, and this is translated into improved symptom control and improved quality of life, even in patients already deemed clinically stable on an oral agent or on a conventional depot antipsychotic.

The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists.

A nationwide survey in 2003 of 300 randomly selected psychiatrists who routinely treat schizophrenia with atypical antipsychotic therapy was conducted to ascertain practice patterns and attitudes regarding metabolic disturbances during atypical antipsychotic therapy with an emphasis on how these perceptions impact therapeutic decision making. Psychiatrists generally believe that some atypical antipsychotic drugs are associated with metabolic disturbances and that atypical antipsychotics differ in their risk for metabolic disturbances. A majority of respondents (82%) believed that patients with schizophrenia-even those not receiving atypical antipsychotic therapy-are at greater risk for metabolic abnormalities than the general population. A majority of respondents recognized weight gain and diabetes mellitus (59% and 51%, respectively) as potential metabolic complications of atypical antipsychotic therapy, while only some recognized dyslipidemia and certain acute metabolic decompensations like diabetic ketoacidosis (22% and 2%, respectively). Large minorities of respondents (48% and 43%) indicated a willingness to risk weight gain and/or diabetes for the benefits of atypical antipsychotics, possibly because metabolic issues were regarded as long-term issues. However, large majorities also stated that they considered metabolic issues when selecting atypical antipsychotic therapy for some or all of their patients (90%), and that emergence of metabolic dysfunction prompted them to change atypical antipsychotic treatment regimens (85%). Additional efforts at continuing education and communication regarding metabolic outcomes associated with atypical antipsychotic therapy, as well as critical reviews in this area, may help clarify atypical antipsychotic treatment risks and benefits. The results from the survey indicate that psychiatrists are aware of and concerned about metabolic risks and how they differ across the atypical antipsychotic class. The impact of additional data and educational efforts in this area, such as a recently published consensus statement from the American Diabetes Association and other organizations, remains to be assessed.

Mechanism of new antipsychotic medications: occupancy is not just antagonism.

Antagonism of D2-like dopamine receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic drugs. Positron emission tomographic studies suggest that the antipsychotic effect of dopamine receptor antagonists occurs within a therapeutic window between 60% and 80% (striatal) D2 receptor occupancy. The incidence of extrapyramidal side effects increases above the 80% threshold. However, the novel atypical antipsychotic drug, aripiprazole, occupies up to 95% of striatal D2-like dopamine receptors at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole is no higher than with placebo. The most likely explanation for this finding is aripiprazole's weak partial agonism at D2-like dopamine receptors. This particular pharmacologic feature characterizes a new class of atypical antipsychotics that does not match the original concept of a therapeutic occupancy window for antagonist antipsychotics. When not involving pure antagonists, it implies a need to adjust the expected receptor occupancy (measured using positron emission tomography) for the therapeutic window.

Safety and tolerability: How do second-generation atypical antipsychotics compare?

Previously, clinicians could only utilize antipsychotic drugs that almost invariably caused extrapyramidal side effects (EPS) at the dose at which they were clinically effective. By definition, second-generation atypical antipsychotic agents are significantly better than conventional agents with regard to EPS; that is, they are clinically effective at doses at which they are less likely to cause EPS. This advantage translates into several important clinical benefits, including better negative symptom efficacy, lesser dysphoria, less impaired cognition, and a lower risk of tardive dyskinesia; in fact, this “EPS advantage” is the principal basis of the clinical advantages provided by this class of atypical antipsychotics. Pharmacologically, “atypical” antipsychotics differ in their side-effect profiles. Six second-generation antipsychotics are currently available in the United States: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. There are meaningful differences between these agents with regard to weight gain, sedation, anticholinergic side effects, cardiovascular issues, endocrine side effects, and hepatic and sexual issues; these are considered and their clinical implications discussed.

Effects of Typical and Atypical Antipsychotics on the Prepulse Inhibition of the Startle Reflex in Patients With Schizophrenia

Patients with schizophrenia show a loss of sensory (motor) gating, which is reflected in a reduced prepulse inhibition (PPI) of the startle reflex. Furthermore, patients with schizophrenia habituate less than healthy subjects. From previous studies, it is clear that typical antipsychotics have little or no effect on either sensorimotor gating or habituation, while only limited data is available on the effects of atypical antipsychotics on these processes.Forty-four schizophrenic patients (27 stable on typical and 17 stable on atypical antipsychotics) and 35 healthy control subjects were tested in a PPI paradigm. The prepulse and startle stimuli were pure tones of 1500 Hz (duration 40 ms, intensity 80 dB and 110 dB respectively), with a fixed interstimulus interval of 120 milliseconds. Block effects in PPI and startle amplitude to the pulse alone trials (habituation) were analyzed over the three groups, using comedication (i.e., benzodiazepines) as a covariate. Main effect for block was found for startle amplitude (habituation), while main effects for group and block were found for percentage PPI. Further analysis displayed significant differences in PPI between the patients treated with typical antipsychotics and the healthy control group, while patients treated with atypical antipsychotics did not differ from either the healthy control group, or the patients treated with typical antipsychotics. Furthermore, post-hoc division of the patients treated with atypical antipsychotics in patients treated with clozapine and risperidone revealed that this superiority from atypical antipsychotics over typical antipsychotics appeared to be mainly based on the effects of clozapine. Patients with schizophrenia who are treated with atypical antipsychotics appear to have levels of sensorimotor gating that are more consistent with healthy controls than patients who are treated with typical antipsychotics. Furthermore, within the class of atypical antipsychotics, clozapine appears most potent in restoring this process.

The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia.

In this paper the historical and scientific background that led to the use of substituted benzamides in two apparently unrelated clinical conditions namely dysthymic disorder and schizophrenia will be reviewed, in order to understand if a common mechanism of action may support this dual therapeutic indication. The dopaminergic antidepressant action of substituted benzamides such as sulpiride, has been proposed, since the late 1970s, by several authors and extensively explored in preclinical experiments by our group. In Italy the first marketing authorization obtained for the new substituted benzamide amisulpride, was with the sole indication of dysthymia and therefore a solid clinical experience exists in the use of substituted benzamides in mild forms of depression, with more than 1 000 000 patients being treated in the last 7 years. The proposed mechanism of action of substituted benzamides implies a selective modulation of the dopaminergic system in the mesocorticolimbic area, important for cognitive processing of internal and external cues, related to survival. The selective antagonism of dopamine D2-D3 receptors has been evoked to explain, in small to moderate doses (ie 50-100 mg day(-1)), the antidepressant effect and, in moderate to medium doses (100-400 mg day(-1)), the reported efficacy on negative symptoms of schizophrenia. Thus, substituted benzamides could represent the first class of atypical antipsychotics successfully employed for both depressive states and schizophrenia. Interestingly, recent evidence in the literature suggests that depressive episodes belonging to the bipolar spectrum are among "alternative indications" of other atypical antipsychotics such as olanzapine and risperidone.

Aripiprazole.

Aripiprazole is a quinolinone derivative and the first of a new class of atypical antipsychotics. The drug has partial agonist activity at dopamine D(2) and serotonin 5-HT(1A) receptors, and is also an antagonist at 5-HT(2A) receptors. In patients with acute relapse of schizophrenia or schizoaffective disorder, aripiprazole 15 to 30 mg/day was at least as effective as haloperidol 10 mg/day and had similar efficacy to risperidone 6 mg/day in well designed, 4-week, placebo-controlled trials. Negative symptoms improved earlier in the aripiprazole than the risperidone group. Efficacy of aripiprazole was observed at week 1 in several trials and was sustained throughout the study periods. Aripiprazole was superior to placebo in a 26-week trial in patients with stable, chronic schizophrenia. In a 52-week trial involving patients with acute relapsing disease, aripiprazole was similar to haloperidol as assessed by time to failure to maintain response and was superior in ameliorating negative and depressive symptoms. The incidence of extrapyramidal symptoms during aripiprazole therapy was similar to that with risperidone and placebo but lower than with haloperidol. Compared with placebo, the proportion of patients with increased plasma prolactin levels and QTc prolongation was similar in patients treated with aripiprazole 15 to 30 mg/day but was significantly increased with haloperidol and risperidone.

Ziprasidone: profile on safety

Ziprasidone (Geodon™, Pfizer) is the latest of a new class of atypical antipsychotics, following the release of clozapine, risperidone, olanzapine and quetiapine. It has a serotonin Type 2a/dopamine Type 2 (5-HT2a/D2) receptor (R) binding ratio of approximately 8:1; amongst the highest of its class. Furthermore, it is a potent 5-HT1aR agonist, and displays 5-HT1dR and 5-HT2cR antagonist activity, with unique effects on blocking the re-uptake of both 5-HT and noradrenaline (NE). Finally, ziprasidone has low-to-modest affinity for histamine (H1) and α1-adrenoceptors and a negligible affinity for muscarinic (M1) Rs. This combination of effects may be responsible for its low rate of general adverse events, low rate of persistent prolactin elevation, low incidence of weight gain, low liability for inducing movement disorders, low rate of syncope and induction of decreases in lipid profile. Data on the effect of ziprasidone on the electrocardiogram (ECG) indicates a relatively higher degree of change in measure of QTc but no cases of mortality from overdoses, torsade de pointes (TdP) or excess in sudden and unexpected deaths.