Third-generation Antipsychotics Research Articles

Impulse control disorders due to cocaine and synthetic stimulants use: a systematic review

The introduction of ICD-11 has opened up new horizons in understanding the impact of modern narcotic substances on mental health, in particular, it has increased the list of possible mental disorders associated with drug use. The purpose of the work is to conduct a systematic review of the literature and describe the features of the pathogenesis, clinical picture, and effectiveness of various types of therapy for impulse control disorders associated with use of cocaine and synthetic stimulants. A systematic analysis of scientific publications was performed in the eLibrary, PubMed, CNKI, and Google Scholar databases according to PRISMA recommendations. 41 publications were selected from the initially found 4,953 articles. The pathogenesis of induced impulse control disorders is associated with the direct effect of stimulant drugs on the brain and consists in the activation of D3 and 5‑HT1A receptors, as well as activation of limbic brain regions and a lack of inhibitory effects of the frontal lobe. Increased impulsivity in users of cocaine and synthetic stimulants has been proven in a large number of neurophysiological and neuroimaging studies. The frequency of occurrence, clinical features, and approaches to therapy of impulse control disorders resulting from the use of drugs with dopaminergic action (drugs for the treatment of Parkinson's disease and hyperprolactinemia, third-generation antipsychotics, and venlafaxine in high doses) have been described in details. At the same time, there is indirect evidence that cocaine and synthetic stimulants should cause impulse control disorders, since they have similar neurotransmitter activity. In addition, there are descriptions of the predominance of individual symptoms of impulse control disorders in this group of drug users. However, at the time of the review, no detailed description of these drug-induced disorders has been found. These are the prospects for further research. The use of fluoxetine and oxcarbazepine (for intermittent explosive disorder) and naltrexone (for kleptomania), as well as comprehensive prevention of drug use relapse and psychotherapy, has the highest degree of evidence as a therapy for impulse control disorders.

New Therapeutic Targets and Drugs for Schizophrenia Beyond Dopamine D2 Receptor Antagonists.

Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field.

Third-Generation Antipsychotics and Lurasidone in the Treatment of Substance-Induced Psychoses: A Narrative Review

This narrative review explores the efficacy and tolerability of third-generation antipsychotics (TGAs)—aripiprazole, cariprazine, brexpiprazole, and lurasidone—for the management of substance-induced psychosis (SIP). SIP is a psychiatric condition triggered by substance misuse or withdrawal, characterized by unique features distinct from those of primary psychotic disorders. These distinctive features include a heightened prevalence of positive symptoms, such as hallucinations and delusions, in addition to a spectrum of mood and cognitive disturbances. This review comprehensively investigates various substances, such as cannabinoids, cocaine, amphetamines, and LSD, which exhibit a greater propensity for inducing psychosis. TGAs exhibit substantial promise in addressing both psychotic symptoms and issues related to substance misuse. This review elucidates the distinctive pharmacological properties of each TGA, their intricate interactions with neurotransmitters, and their potential utility in the treatment of SIP. We advocate for further research to delineate the long-term effects of TGAs in this context and underscore the necessity for adopting an integrated approach that combines pharmacological and psychological interventions. Our findings underscore the intricate and multifaceted nature of treating SIP, highlighting the potential role of TGAs within therapeutic strategies.

Serum Interleukin-6 in Schizophrenia: Associations with Clinical and Sociodemographic Characteristics.

Recently a significant part of schizophrenia studies have been focused on the role of cytokines, especially interleukin-6 (IL-6). Some authors have suggested a pathogenetic role for IL-6 in schizophrenia and concluded that therapy that centers on suppressing IL-6 activity may prove beneficial for certain categories of patients with the disorder. However, many questions about whether the changes in IL-6 levels in schizophrenia are primary, related to symptoms or caused by therapy, are concomitant metabolic disorders, are related to smoking or other secondary factors remain unanswered. To assess the level of serum IL-6 in patients with schizophrenia in comparison with healthy controls, as well as to study its association with clinical and socio-demographic characteristics. Some 125 patients with schizophrenia and 95 healthy volunteers were examined. The evaluation of IL-6 was performed by enzyme immunoassay. All patients were assessed using standardized psychometric instruments. Information from patient medical records on the course of the disease and treatment was analyzed. The level of IL-6 was significantly higher in the patients than in the healthy volunteers (z=2.58; p=0.0099), but among men the difference between the patients and volunteers was not significant. Statistically significant correlations were found between the level of serum IL-6 and the severity of the cognitive impairment of patients: (auditory [ρ=-0.31; p=0.00063] and working memory [ρ=-0.25; p=0.0065], hand-eye coordination [ρ=-0.29; p=0.0011], verbal fluency [ρ=-0.28; p=0.0019] and problem-solving capacity [ρ=-0.22; p=0.013]), total severity of schizophrenia symptoms (PANSS, ρ=0.22; p=0.016), PANSS positive subscale (ρ=0.18; p=0.048), and the age of manifestation (ρ=0.20; p=0.025) and disease duration (ρ=0.18; p=0.043). The level of IL-6 was the lowest in patients treated with third-generation antipsychotics, and the highest in those treated with first-generation antipsychotics (H=6.36; p=0.042). Moreover, in hospital patients, the level of IL-6 was significantly higher than in outpatients and inpatients hospitals (H=18.59; p=0.0001). The study confirmed that there are associations between the serum IL-6 level and schizophrenia, the age of the patient, duration of the disease and how late in one's life cycle it began manifesting itself, as well as a number of clinical characteristics. Considering that IL-6 is associated with a wide range of symptoms that are loosely controlled by antipsychotics, this biochemical marker needs to be studied to look into how closely its level tracks with an unfavorable course of schizophrenia. That would require further prospective studies.

The phenomenon of therapeutic resistance in the treatment of schizophrenia: the possibilities of modern diagnostics and methods of anti-resistant effects

The formation of resistance is a key factor in curbing progress in the treatment of schizophrenia. In modern psychiatric practice, despite the emergence of new medical technologies, including the use of a wide arsenal of psychotropic medicinal effects, the frequency of manifestations of therapeutic resistance in the cohort of mentally ill is on average about 30%. The reasons for the formation of resistance identified to date are diverse and can be associated with both biological changes due to violations of the functioning of various neurotransmitter systems. so it is with non-compliance with the regimen of taking medications (drug noncompliance). Therapy-resistant schizophrenia is a serious clinical problem, since patients with such manifestations often feel the need for repeated hospitalizations, have more pronounced violations of social and professional functioning. It has been established that the formation of therapeutic resistance can occur both at the beginning of active treatment and in the process of psychopharmacotherapy. Therefore, it is important to identify predictors of therapeutic resistance, which will allow using methods to overcome it as soon as possible. This literature review examines both the main forms of therapeutic resistance and the features of its formation, as well as the possibilities of drug and non-drug therapy of resistant schizophrenia.Materials and methods. A literature review was performed in the PubMed database. The keywords types of therapeutic resistance, therapeutically resistant schizophrenia, antipsychotics, methods of anti-resistant effects. Inclusion criteria: randomized and non-randomized clinical trials, meta-analyses and systematic reviews, fulltext articles on therapeutic resistance in mentally ill patients and coping methods. Exclusion criteria: articles of poor quality. Results. The analysis of the literature data has shown the expediency of using not only clozapine, a first-line drug, for therapeutic resistance, but also modern drugs, primarily cariprazine, which, despite limited studies, have shown high efficacy both in combination therapy with clozapine and in monotherapy, in correcting stable productive, negative and cognitive symptoms. The use of augmentation with antidepressants, normotimic and glutamatergic drugs can be used to overcome resistance, but data on the effectiveness of this strategy are ambiguous. Of the non-medicinal methods of treating therapeutically resistant schizophrenia, the use of electroconvulsive therapy is recommended as the only method of biological effects that currently has an evidence base. Conclusions. According to the results of the literature review, the most studied, proven methods of overcoming therapeutically resistant schizophrenia are clozapine and electroconvulsive therapy. At the same time, taking into account the preliminary positive results of the use of third-generation antipsychotics, it can be considered appropriate to use them both in combination therapy and in monotherapy, with insufficient effectiveness of clozapine.

Could Cariprazine Be a Possible Choice for High Functioning Autism? A Case Report

This case report was conducted by searching for the following keywords on PubMed: High Functioning Autism, Autism Spectrum Disorder, cariprazine, aripiprazole, partial agonist antipsychotic, DRD2/DRD3. High Functioning Autism (HFA) is a neurodevelopmental disorder characterized by the core symptoms of autism spectrum disorder (ASD) with average intellectual abilities, behavioral symptoms such as irritability, hyperactivity, aggressiveness and mood symptoms. HFA is not a term used in the Diagnostic and Statistical Manual of mental disorders (DSM), but it is commonly used to identify patients diagnosed with Autistic Disorder (AD) or Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) with average or above average intellectual abilities. Several factors are involved in HFA development, including environmental and genetic factors. In particular, over the last several decades, dopaminergic signaling system dysfunction has been highlighted as being responsible for behavioral patterns. Nowadays, symptoms of ASD lack a specific pharmacological treatment. The only medications approved by the Food and Drug Administration (FDA) for symptoms associated with ASD, in particular the irritability, are risperidone and aripiprazole. According to the hypothesis that dopamine receptor DRD2 and DRD3 might be involved in impulsive behavior, stereotypy, repetitive behaviors and language impairment, cariprazine could be a therapeutic option. This molecule is primarily characterized by DRD3 partial agonism and serotonin 5-HT1A partial agonism, with a lower ability to activate DRD2 than other third-generation antipsychotics, such as aripiprazole. We have reported here a case study of treatment of HFA with cariprazine.

Aripiprazole and Other Third-Generation Antipsychotics as a Risk Factor for Impulse Control Disorders: A Systematic Review and Meta-Analysis.

Increasing evidence suggests an association between third-generation antipsychotics (TGAs) and impulse control disorders (ICDs). This is thought to be due to their partial agonism of dopamine receptors. However, neither the relative nor absolute risks of ICDs in those prescribed TGAs are well established. To inform clinical practice, this systematic review and meta-analysis summarizes and quantifies the current evidence for an association. An electronic search of Medline, PsychINFO, EMBASE, and the Cochrane Clinical Trials Database was undertaken from database inception to November 2022. Three reviewers screened abstracts and reviewed full texts for inclusion. A random-effects meta-analysis was conducted with eligible studies. A total of 392 abstracts were retrieved, 214 remained after duplicates were removed. Fifteen full texts were reviewed, of which 8 were included. All 8 studies found that TGAs were associated with increased probability of ICDs. Risk of bias was high or critical in 7 of 8 studies. Three studies were included in the pooled analysis for the primary outcome, 2 with data on each of aripiprazole, cariprazine, and brexpiprazole. Exposure to TGAs versus other antipsychotics was associated with an increase in ICDs (pooled odds ratio, 5.54; 2.24-13.68). Cariprazine and brexpiprazole were significantly associated with ICDs when analyzed individually. Aripiprazole trended toward increased risk, but very wide confidence intervals included no effect. Third-generation antipsychotics were associated with increased risk of ICDs in all studies included and pooled analysis. However, the risk of bias is high, confidence intervals are wide, and the quality of evidence is very low for all TGAs examined.

Volumetric absorptive microsampling for the therapeutic drug monitoring of psychiatric patients treated with cariprazine

Psychiatric disorders are usually treated with antipsychotic agents belonging to different pharmacological and chemical classes, the most recent ones collectively known as “third-generation antipsychotics”, such as cariprazine, approved in 2015 for the treatment of patients affected by schizophrenia. For these patients, a frequent therapeutic drug monitoring (TDM) becomes essential to assess compliance and to optimise and personalise their therapy, also due to cariprazine interindividual variability and narrow therapeutic range. In this study, a bioanalytical method featuring miniaturised sampling and pretreatment was developed, based on volumetric absorptive microsampling (VAMS) for TDM of psychiatric patients under cariprazine treatment and compared to a reference method based on fluid plasma analysis.Minimally invasive whole blood VAMS was coupled to an original instrumental method based on ultra-high performance liquid chromatography hyphenated to mass spectrometry (UHPLC-MS). A feasible and streamlined, yet reliable VAMS pretreatment protocol was carefully optimised and the VAMS-UHPLC-MS methodology was validated with satisfactory results in terms of linearity (r2 > 0.9970 in the 1.5–100 ng/mL range), precision (%RSD < 11.7), extraction yield (> 90.0 %) and matrix effect (8.2 ≤ %RE ≤ 10.9). Finally, the microsampling approach coupled to UHPLC-MS was successfully applied to the TDM of psychiatric patients treated with cariprazine and compared with standard fluid plasma analysis, providing reliable quali-quantitative results, and proving to be readily applicable to the clinical practice in TDM programs as a useful alternative to cariprazine plasma analysis. This is the first report of a successful microsampling application, and in particular the first report of VAMS application, for the TDM of cariprazine.

Transformation of a Dopamine D2 Receptor Agonist to Partial Agonists as Novel Antipsychotic Agents.

Designed ligands of G protein-coupled receptors can exert a spectrum of modulating effects, varying from full agonists and partial agonists to antagonists and inverse agonists. For the dopamine D2 receptor (D2R), partial agonist activity is the pharmacological feature of the third-generation antipsychotics, including aripiprazole, brexpiprazole, and cariprazine. Started from a benzofuran-derived D2R full agonist O4LE6 (4), which was identified using a structure-based method by us in previous studies, a series of D2R partial agonists were designed and synthesized by introducing different tail groups. Among them, compound 10b showed excellent activity in D2R pharmacological assays. Further optimizations using a structural rigidification approach led to the discovery of brain-penetrant compounds 29c and 29d, which exhibited potent antipsychotic effects in the mouse hyperlocomotion model. Compound 29c also showed excellent drug-like pharmacokinetic properties in rats and qualifies as an antipsychotic agent that is worth further evaluations.

Application of Antipsychotic Drugs in Mood Disorders.

Since their first application in psychiatry seventy years ago, antipsychotic drugs, besides schizophrenia, have been widely used in the treatment of mood disorders. Such an application of antipsychotics is the subject of this narrative review. Antipsychotic drugs can be arbitrarily classified into three generations. First-generation antipsychotics (FGAs), such as phenothiazines and haloperidol, were mainly applied for the treatment of acute mania, as well as psychotic depression when combined with antidepressants. The second-generation, so-called atypical antipsychotics (SGAs), such as clozapine, risperidone, olanzapine, and quetiapine, have antimanic activity and are also effective for the maintenance treatment of bipolar disorder. Additionally, quetiapine exerts therapeutic action in bipolar depression. Third-generation antipsychotics (TGAs) started with aripiprazole, a partial dopamine D2 receptor agonist, followed by brexpiprazole, lurasidone, cariprazine, and lumateperone. Out of these drugs, aripiprazole and cariprazine have antimanic activity, lurasidone, cariprazine, and lumateperone exert a significant antidepressant effect on bipolar depression, while there is evidence for the efficacy of aripiprazole and lurasidone in the prevention of recurrence in bipolar disorder. Therefore, successive generations of antipsychotic drugs present a diverse spectrum for application in mood disorders. Such a pharmacological overlap in the treatment of schizophrenia and bipolar illness stands in contrast to the dichotomous Kraepelinian division of schizophrenia and mood disorders.

Third-generation antipsychotics in patients with schizophrenia and non-responsivity or intolerance to clozapine regimen: What is the evidence?

Clozapine is considered « the golden standard » for the management of treatment-resistant schizophrenia, but many patients do not present adequate responsivity even to this antipsychotic. If we add the need to strictly monitor the hematologic and cardiometabolic adverse events during each clozapine trial and the difficulty of preserving therapeutic adherence in patients with low insight, residual negative/positive symptoms, or economic challenges, then the necessity of exploring alternative interventions for these patients becomes obvious. Also, in case of intolerance to clozapine or where clozapine did not induce remission, clinicians have to find new ways to help their patients. Switching to other antipsychotics or using these agents as add-ons to clozapine are the main interventions explored in this review, for patients with schizophrenia resistant to clozapine (ultra-resistant schizophrenia, URS). When clozapine intolerance is detected, conversion to another antipsychotic with distinct pharmacologic properties or formulation (e.g., long-acting intramuscular injectable agents, LAI) may be a useful option. Third-generation antipsychotics (TGA) have been selected for their distinct pharmacodynamically profile, which allows, at a theoretical level, their use in combination with clozapine. This narrative review is based on searching four electronic databases, that retrieved 19 primary and secondary reports on aripiprazole (seven case reports or case series presenting 24 patients; nine clinical trials, and three systematic reviews/meta-analyses), two primary reports on brexpiprazole (case report and case series, N = 3 patients), and six primary reports on cariprazine (case reports and case series, N = 14 patients). Based on the information collected from these reports, which included oral and LAI formulations, the TGA most supported by evidence for the augmentation of clozapine is aripiprazole (high-and medium-quality data), followed by cariprazine (low-quality data). Brexpiprazole has not yet been systematically explored for this indication, and in the case of lumateperone, no report could be found. The efficacy of aripiprazole and cariprazine was supported in the domains of positive, negative, and general symptoms, and aripiprazole may positively impact the metabolic profile in patients with URS. Also, adding TGA may lead to a decrease in the dose of clozapine concomitantly administered. More data derived from good quality research are needed in order to confirm the circumstances of TGAs recommendation in patients with URS, either as monotherapy, or added to clozapine.

Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System.

BackgroundThe dopaminergic partial agonism of the so-called third-generation antipsychotics (TGAs; aripiprazole, brexpiprazole, cariprazine) is hypothesized to cause impulse control disorders (ICDs). Relevant warnings by the Food and Drug Administration (FDA) were posted on aripiprazole (2016) and brexpiprazole (2018). Our study investigated the FDA Adverse Event Reporting System and the pharmacodynamic CHEMBL database to further characterize TGA-induced ICDs.MethodsWe downloaded and pre-processed the FDA Adverse Event Reporting System up to December 2020. We adapted Bradford Hill criteria to assess each TGA’s —and secondarily other antipsychotics’—causal role in inducing ICDs (pathological gambling, compulsive shopping, hyperphagia, hypersexuality), accounting for literature and disproportionality. ICD clinical features were analyzed, and their pathogenesis was investigated using receptor affinities.ResultsA total of 2708 reports of TGA-related ICDs were found, primarily recording aripiprazole (2545 reports, 94%) among the drugs, and gambling (2018 reports, 75%) among the events. Bradford-Hill criteria displayed evidence for a causal role of each TGA consistent across subpopulations and when correcting for biases. Significant disproportionalities also emerged for lurasidone with compulsive shopping, hyperphagia, and hypersexuality, and olanzapine and ziprasidone with hyperphagia. Time to onset varied between days and years, and positive dechallenge was observed in 20% of cases. Frequently, co-reported events were economic (50%), obsessive-compulsive (44%), and emotional conditions (34%). 5-Hydroxytryptamine receptor type 1a agonism emerged as an additional plausible pathogenetic mechanism.ConclusionsWe detected an association between TGAs and ICDs and identified a new signal for lurasidone. ICD characteristics are behavior specific and may heavily impact on life. The role of 5-Hydroxytryptamine receptor type 1a agonism should be further explored.

Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.

Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a 'bolt'. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation.

Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and β-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.

Antipsychotics cardiotoxicity: What's known and what's next.

Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling, sometimes life-shortening adverse effects. Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns. These cardiotoxic effects range from arrhythmia to heart failure in the clinic, with myocarditis/cardiomyopathy, ischemic injuries, and unexplained cardiac lesions as the pathological bases. Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity. This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level. We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity. We propose that third-generation antipsychotics or drug adjuvant therapy, such as cannabinoid receptor modulators that confer dual benefits — i.e., alleviating cardiotoxicity and improving metabolic disorders — deserve further clinical evaluation and marketing.

Amantadine for the treatment of childhood and adolescent psychiatric symptoms

This retrospective study examined clinical parameters associated with amantadine treatment of psychiatric symptoms in children. A total of 297 pediatric patients were prescribed amantadine and met study criteria to assess clinical responses and medication outcomes. More than 62% of patients experienced clinically significant symptom control and 83% achieved at least maintenance symptom control, while 11% discontinued amantadine for nonresponse and 6% stopped amantadine because of side effects. Among patients previously receiving other psychotropic medication, 42% and 28% of patients fully discontinued second- or third-generation antipsychotics or antidepressants, respectively. Patients responsive to amantadine who discontinued or reduced antipsychotic dose experienced a significant reduction in body mass index. Amantadine appears be an efficacious and safe alternative for treatment of a broad set of psychiatric symptoms in children and adolescents. Specifically, it may serve as an effective adjunct to stimulants for attention deficit/hyperactivity disorder–related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics.

Third-generation antipsychotics: focus on cariprazine

Antipsychotic drugs represent a fundamental aid for the treatment of schizophrenia and other psychiatric disorders. However, the definition of antipsychotics includes molecules that are extremely heterogeneous when considering their mechanism of action and the clinical implications. While in the first part of this review the major critical issues in the treatment of schizophrenia will be highlighted, the attention will then focus on the major pharmacological 'innovation' in recent years, which is represented by the development of partial agonists for the D2 and D3 receptors, a strategy that may guarantee a 'stabilization' of impaired dopaminergic function in the schizophrenic patient. One such drug is cariprazine that differs from other molecules due to its greater affinity for the dopaminergic D3 receptor. Next, it will be described receptor and functional mechanisms that characterize the action of cariprazine, both with respect to other partial agonists as well as with respect to second-generation antipsychotics. More specifically, it will be highlighted the peculiarities of cariprazine and how these mechanisms could modify the functionality of specific brain circuits associated with major functional domains that are altered in schizophrenia. The activity of partial agonist at dopaminergic D3 receptors, which is dominant as compared to other receptor mechanisms, represents the mechanism that is most likely associated with the improvement of negative symptoms and of specific components such as motivational deficits. Furthermore, this mechanism together with the binding to other receptors is also compatible with a positive effect on cognitive deficits, often associated with reduced functionality of the prefrontal cortex, as well as in the substance abuse, a relevant problem of co-morbidity with schizophrenia.

L’aripiprazole comme modèle d’agoniste dopaminergique partiel : concepts de base et incidence clinique

Aripiprazole may be viewed as the prototype of third-generation antipsychotics. This concept is based on the notion of D2 partial agonism, whereas all molecules of first–and second generation were D2 antagonists. After reviewing the basic pharmacological notions linked to such concepts, the mechanisms of action of these molecules are addressed, with a particular focus on functional selectivity and biased ligand. One of the essential pharmacological properties of D2 agonists, and particularity aripiprazole, is their ability to not induce D2 supersensitivity as well as to reverse this supersensitivity when it has been induced by D2 antagonists. In clinical practice, this impacts the choice of treatment in first episode psychosis as well as in refractory schizophrenia. Animal research shows that D2 supersensitivity could contribute to worsen addictive trends. The pharmacokinetic incidence of D2 supersensitivity tends to favour the long-acting forms of partial agonists. The notion of partial agonism could finally lead to design fourth-generation antipsychotics, on the basis on research focusing on functional selectivity.

Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors.

Tardive dyskinesia (TD) encompasses the spectrum of iatrogenic hyperkinetic movement disorders following exposure to dopamine receptor-blocking agents (DRBAs). Despite the advent of atypical or second- and third-generation antipsychotics with a presumably lower risk of complications, TD remains a persistent and challenging problem. Prevention is the first step in mitigating the risk of TD, but early recognition, gradual withdrawal of offending medications, and appropriate treatment are also critical. As TD is often a persistent and troublesome disorder, specific antidyskinetic therapies are often needed for symptomatic relief. The vesicular monoamine transporter 2 (VMAT2) inhibitors, which include tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice for most patients with TD. Deutetrabenazine-a deuterated version of tetrabenazine-and valbenazine, the purified parent product of one of the main tetrabenazine metabolites, are novel VMAT2 inhibitors and the only drugs to receive approval from the US FDA for the treatment of TD. VMAT2 inhibitors deplete presynaptic dopamine and reduce involuntary movements in many hyperkinetic movement disorders, particularly TD, Huntington disease, and Tourette syndrome. The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding. Compared with tetrabenazine, deutetrabenazine and valbenazine have pharmacokinetic advantages that translate into less frequent dosing and better tolerability. However, no head-to-head studies have compared the various VMAT2 inhibitors. One of the major advantages of VMAT2 inhibitors over DRBAs, which are still being used by some clinicians in the treatment of some hyperkinetic disorders, including TD, is that they are not associated with the development of TD. We also briefly discuss other treatment options for TD, including amantadine, clonazepam, Gingko biloba, zolpidem, botulinum toxin, and deep brain stimulation. Treatment of TD and other drug-induced movement disorders must be individualized and based on the severity, phenomenology, potential side effects, and other factors discussed in this review.

Deuterium Tetrabenazine for Tardive Dyskinesia.

Tardive dyskinesia remains a significant, potentially stigmatizing or crippling adverse effect for any patient treated with an antipsychotic medication. While second- and third-generation antipsychotics have exhibited lower annual incidence rates for tardive dyskinesia than classic or first-generation agents, 3.9% versus 5.5%, the estimated incidence rate is only modestly lower. When coupled with the fact that second- and third-generation antipsychotic medications have come to be employed in treating a wider range of disorders (e.g., autism spectrum disorders, mood disorders, personality disorders, etc.), it is clear that the population of patients exposed to the risk of tardive dyskinesia has expanded. On April 3, 2017, the U.S. Food and Drug Administration (FDA) approved a deuterated version of tetrabenazine (Xenozine®) for the treatment of the involuntary choreic movements associated with Huntington's disease. More recent data, however, have indicated that deuterium tetrabenazine or deutetrabenazine (Austedo®) is effective in treating tardive dyskinesia. Moreover, like the other derivative of tetrabenazine, valbenazine (Ingrezza®), deutetrabenazine offers less frequent dosing and a better short-term adverse effect profile than that of tetrabenazine. Longer use in a broader range of patients, however, will be required to identify risks and benefits not found in short-term trials, as well as optimal use parameters for treatment of tardive dyskinesia.