Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities

Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine’s efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.

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Aripiprazole once-monthly efficacy in patients with schizophrenia. Review

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.2159 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S582-S582

Author(s):

M.F. Molina López ◽

M.C. Cancino Botello ◽

A. Peña Serrano ◽

M.D.L.A. Canseco Navarro

Keyword(s):

Quality Of Life ◽

Negative Symptoms ◽

Partial Agonist ◽

Emotional Interaction ◽

Medication Delivery ◽

Pubmed Database ◽

Competing Interest ◽

Long Acting

Introductionlong acting injectable formulations of antipsychotics are a valuable option for patients with schizophrenia, offering continuous medication delivery and stable dosage levels. Aripiprazole once-monthly is the first dopamine partial agonist available in long acting formulation approved in Europe for Schizophrenia with excellent results so far.Aimsto conduct a current review of articles related to the use and efficacy of Aripiprazole once monthly in patients with Schizophrenia.Methodssystematic review of the literature in English using the following keywords: “aripiprazole once-monthly”, “aripiprazole long acting formulation”, “schizophrenia”. PubMed database.ResultsAripiprazole once-monthly (AOM) formulation efficacy has been proven in many studies. The importance of maintaining an oral overlap during 14 days is highlighted in all studies that have been reviewed in order to reach therapeutic level; therefore, it can be used in patients with acute decompensations. Recent studies comparing AOM versus Paliperidone Palmitate once monthly (PP) have shown that patients with AOM had greater clinical improvement and, even though both drugs were well tolerated, when Quality of Life Style Scale was analyzed an important improvement in empathy, sense of purpose, emotional interaction and curiosity in the AOM group was observed.Conclusionslong acting injectable antipsychotics increase long-term adherence treatment and reduce risk of relapse. Because of its unique mechanism of action, Aripiprazole once-monthly improves positive and negative symptoms, giving the patient an opportunity to have a better quality of life.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Recycling N-acetylcysteine: A review of evidence for adjunctive therapy in schizophrenia

Mental Health Clinician ◽

10.9740/mhc.2019.05.116 ◽

2019 ◽

Vol 9 (3) ◽

pp. 116-123 ◽

Cited By ~ 1

Author(s):

Robert J. Willborn ◽

Colleen P. Hall ◽

Matthew A. Fuller

Keyword(s):

Negative Symptoms ◽

Current Evidence ◽

Positive Symptoms ◽

Cognitive Symptoms ◽

Antipsychotic Therapy ◽

Assessment Development ◽

Cognitive Symptom ◽

Symptom Domains ◽

Medication Intervention

AbstractIntroductionAll symptoms in schizophrenia may impact functioning. Although Food and Drug Administration-approved medications typically benefit positive symptoms, negative symptoms are generally refractory to medication interventions. N-acetylcysteine's (NAC) influence on glutamatergic neurotransmission has been established. An emerging body of research has attempted to correlate this action with reduction in symptom severity, evaluating response in positive, negative, and cognitive symptom domains.MethodsA literature review was performed to analyze available data on NAC intervention and improvement in the positive, negative, and cognitive symptom domains in patients with schizophrenia. Quality of evidence was systematically assessed to determine level of certainty in results.ResultsThree randomized controlled trials were identified. Across studies, negative symptoms decreased more with NAC compared to placebo; ranging between 11.9% and 24.1%. The assessment determined a low level of certainty regarding benefit of NAC on negative and cognitive symptoms and moderate certainty for NAC regarding findings of side effects and lack of benefit on positive symptoms.DiscussionConsistent reporting of benefit in negative symptoms is found across studies of NAC intervention. These improvements are notable for symptoms that have generally remained refractory to medication intervention. Inconsistent benefit was reported in positive and cognitive symptoms. GRADE (grading of recommendations assessment, development and evaluation) assessment of current evidence indicates a low certainty of benefit for negative symptoms with standard use of NAC in patients with schizophrenia. However, a trial of this low-risk intervention may be warranted in patients with resistant negative symptoms and subsequent impaired functioning despite appropriate antipsychotic therapy as they may experience additional benefit in this symptom domain.

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Efficacy of Memantine in Schizophrenic Patients: A Systematic Review

Journal of Amino Acids ◽

10.1155/2017/7021071 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 14

Author(s):

Giuseppe Di Iorio ◽

Gaia Baroni ◽

Marco Lorusso ◽

Chiara Montemitro ◽

Maria Chiara Spano ◽

...

Keyword(s):

Systematic Review ◽

Negative Symptoms ◽

Positive Symptoms ◽

Cognitive Symptoms ◽

Review Of The Literature ◽

Excitatory Neurotransmitter ◽

Aspartate Receptor ◽

Schizophrenic Patients ◽

Promising Treatment

Several evidences support the hypothesis that glutamatergic dysfunction may be implicated in the pathogenesis of schizophrenia and in the last few years great interest has been focused on the role of the N-methyl-D-aspartate receptor (NMDAR). Glutamate is the main excitatory neurotransmitter in human CNS and it plays a prominent role in synaptic plasticity, learning, and memory and other cognitive functions. Increasing interest in memantine add-on therapy in schizophrenic patients with negative and cognitive symptoms may suggest that memantine could be a new promising treatment in schizophrenia. The aim of this update was to evaluate clinical data about the memantine effectiveness in schizophrenic patients. Our systematic review of the literature highlights that memantine therapy in schizophrenic patients seems to improve mainly negative symptoms while positive symptoms and cognitive symptoms did not improve significantly.

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Antipsychotics for negative and positive symptoms of schizophrenia: dose-response meta-analysis of randomized controlled acute phase trials

npj Schizophrenia ◽

10.1038/s41537-021-00171-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Michel Sabe ◽

Nan Zhao ◽

Alessio Crippa ◽

Stefan Kaiser

Keyword(s):

Acute Phase ◽

Dose Response ◽

Negative Symptoms ◽

Meta Analysis ◽

Positive Symptoms ◽

Response Curves ◽

Randomized Controlled ◽

Effective Doses ◽

Dose Response Curves ◽

Long Acting

AbstractDetermining the optimal antipsychotic target dose in acute phase treatment is of high clinical relevance. The effect of antipsychotics on negative symptoms should be taken into account because patients will often continue on the treatment received in the acute phase. Therefore, we conducted a formal dose-response meta-analysis of negative symptoms and positive symptoms based on a systematic review of fixed-dose randomized controlled trials (RCTs) that examined the effectiveness of antipsychotics for the acute exacerbation of schizophrenia. Forty RCTs included a total of 15,689 patients. The 95% effective doses per day for the 13 antipsychotics included and 3 long acting were mostly different for negative and positive symptoms: amisulpride (481 mg, 690.6 mg); aripiprazole (11.9 mg, 11 mg); asenapine (7.61 mg, 5.66 mg); brexpiprazole (2.1 mg, 4 mg); cariprazine (4 mg, 6.51 mg); haloperidol (6.34 mg, 7.36 mg); lurasidone (58.2 mg, 86.3 mg); olanzapine (15.5 mg, 9.52 mg); olanzapine long-acting injection (15.7 mg, 13.5 mg); paliperidone (7.2 mg, 7 mg); paliperidone long-acting injection (7.5 mg, 5.9 mg); quetiapine instant-release (264.2 mg, 316.5 mg); quetiapine extended-release (774 mg, 707.2 mg); risperidone (7.5 mg, 7.7 mg); risperidone long-acting injection (5.13 mg, 6.7 mg); sertindole (13.5 mg, 16.3 mg); and ziprasidone (71.6 mg, 152.6 mg). The shape of the dose-response curves varied across different drugs with most drugs showing a plateau at higher doses. Most dose-response curves suggested that the near-maximum effective doses could be in the lower-to-medium range of the licensed dose. Additional RCTs are necessary to establish the optimal dose.

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Cognitive Dysfunction in Schizophrenia

Jurnal Psikiatri Surabaya ◽

10.20473/jps.v9i2.19082 ◽

2020 ◽

Vol 9 (2) ◽

pp. 52

Author(s):

Susana Anggar Kusuma ◽

Yunias Setiawati

Keyword(s):

Problem Solving ◽

Mental Disorder ◽

Negative Symptoms ◽

Memory Function ◽

Cognitive Disorder ◽

Positive Symptoms ◽

Cognitive Symptoms ◽

Affective Symptoms ◽

Attention Function ◽

Severe Disorder

Schizophrenia is a mental disorder which includes: positive symptoms, negative symptoms, cognitive symptoms, affective symptoms and aggressive symptoms. Cognitive disorder is the most severe disorder compared to other symptoms of schizophrenia because it can interfere with daily functions, including memory function, attention function, problem solving function, speech function and social skills.

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Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine

Acta Neuropsychiatrica ◽

10.1017/neu.2015.1 ◽

2015 ◽

Vol 27 (3) ◽

pp. 159-167 ◽

Cited By ~ 22

Author(s):

Akiko Matsuura ◽

Yuko Fujita ◽

Masaomi Iyo ◽

Kenji Hashimoto

Keyword(s):

Nmda Receptor ◽

Oral Dose ◽

Single Oral Dose ◽

Sodium Benzoate ◽

Negative Symptoms ◽

Nmda Receptor Antagonist ◽

Oxidase Inhibitor ◽

Acid Oxidase ◽

Dependent Manner ◽

Amino Acid Oxidase

ObjectiveA recent clinical study demonstrated that sodium benzoate (SB), a prototype competitive d-amino acid oxidase inhibitor, was effective in the treatment of several symptoms, such as positive and negative symptoms, and cognitive impairment in medicated patients with schizophrenia. The objective of the study was to examine the effects of SB on behavioural abnormalities such as pre-pulse inhibition (PPI) deficits and hyperlocomotion in mice after a single administration of the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP).MethodsThe effects of SB on behavioural abnormalities (PPI deficits and hyperlocomotion) in mice after PCP administration were examined. Furthermore, effects of SB on tissue levels of amino acids were also examined.ResultsA single oral dose of SB (100, 300, or 1000 mg/kg) attenuated PPI deficits in mice after administration of PCP (3.0 mg/kg, s.c.) in a dose-dependent manner. In contrast, L-701,324 (10 mg/kg), an antagonist at the glycine site of the NMDA receptor, did not affect the effect of SB (1000 mg/kg) on PCP-induced PPI deficits. Furthermore, a single oral dose of SB (1000 mg/kg) significantly attenuated the hyperlocomotion in mice after administration of PCP (3.0 mg/kg, s.c.). However, a single oral dose of SB (1000 mg/kg) caused no changes to d-serine levels in plasma or in the frontal cortex, hippocampus, and striatum of these animals.ConclusionThis study suggests that SB induced antipsychotic effects in the PCP model of schizophrenia, although it did not increase d-serine levels in the brain.

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Utilization of Long-Acting Antipsychotic Medication in Patient Care

CNS Spectrums ◽

10.1017/s1092852900025852 ◽

2006 ◽

Vol 11 (S14) ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

John M. Kane

Keyword(s):

Negative Symptoms ◽

Treatment Effectiveness ◽

Treatment Resistance ◽

Well Being ◽

First Episode ◽

Antipsychotic Treatment ◽

Conventional Antipsychotics ◽

Optimal Functioning ◽

Ultimate Outcome ◽

Long Acting

AbstractSchizophrenia is a complex disorder characterized by a broad spectrum of psychopathology. Aggressive efforts to bring the patient into remission should begin immediately after the first episode. Consequences of non-remission include poor prognosis, psychiatric and general medical complications, treatment resistance, and death from medical comorbidities and suicide. Prevention of relapse following remission is critical to the well-being and optimal functioning of patients with schizophrenia.The key to optimizing patients' outcomes is to ensure a patient's long-term continuation on medication. As treatment discontinuation can greatly impact the progression of the illness and the patient's ultimate outcome, selecting a treatment with maximum treatment effectiveness is optimal. Nonadherence to treatment is extremely prevalent among patients with schizophrenia, due to such factors as impaired cognition, lack of insight, and side effects associated with antipsychotic treatment.Atypical antipsychotics have shown some advantages over conventional antipsychotics in terms of reducing positive and negative symptoms of schizophrenia, preventing relapse, and incidence of tardive dyskinesia. Injectables and long-acting formulations of antipsychotics offer additional benefits in terms of ensuring treatment adherence.

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Combined pharmacotherapy involving aripiprazole and clozapine for controlling the positive symptoms refractory to other antipsychotic treatments in a patient with schizophrenia

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.1581 ◽

2017 ◽

Vol 41 (S1) ◽

pp. s814-s814

Author(s):

G. Hernandez Santillan ◽

K. Lazo-Chávez ◽

M. Blanco-Prieto

Keyword(s):

Latin American ◽

Negative Symptoms ◽

Treatment Resistance ◽

Positive Symptoms ◽

Social Functions ◽

Male Resident ◽

Clozapine Therapy ◽

Cultural Aspects ◽

Clozapine Dose ◽

Competing Interest

IntroductionTreatment resistance is considered a challenging problem of antipsychotic pharmacotherapy in schizophrenia, especially, when it is associated with other factors, such as cultural aspects, diverse clinical presentation, furthermore functional impact. Then, combination approaches are commonly used, for instance, the add-on of aripiprazole to clozapine; which allows increasing of efficacy and safety.ObjectiveAssess the response to clozapine–aripiprazole combination treatment in the management of resistant schizophrenia.AimTreatment of resistant schizophrenia.MethodAnalysis of a clinical case.ResultA 27-year-old male resident in an Iberian country two years ago, is from a Latin American country, lives with his mother, his sister and his nephew. Their parents were separated. Eight years ago, his father died and shortly thereafter, he started impaired behavior, auditory and visual hallucinations, delusions about referentiality, persecution and prejudice, which required a brief hospitalization in their country. Upon arrival, he is included in the network of Mental Health, with positive symptoms, significant behavioral and cognitive disorganization and he needed hospitalization again. Then, treatment is instituted in different lines with risperidone, quetiapine, olanzapine, haloperidol, amisulpride, without results. Then, combined clozapine therapy is initiated up to 400 mg/day, more aripiprazole 20 mg/day, which switch after to pattern injectable depot, with informed consent. Six months after, he presents encapsulated delirium and improvement of disorganization, allowing the patient to retake studies.ConclusionClozapine–aripiprazole combination was associated with 22% reduction of clozapine dose. There was improvement in positive and negative symptoms, social functions and amelioration in their metabolic profile.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.742058 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ju-Chun Pei ◽

Da-Zhong Luo ◽

Shiang-Shin Gau ◽

Chia-Yuan Chang ◽

Wen-Sung Lai

Keyword(s):

Nmda Receptor ◽

Cognitive Deficits ◽

Clinical Studies ◽

Negative Symptoms ◽

Cognitive Symptoms ◽

Amino Acid Oxidase ◽

Antipsychotic Medications ◽

Medical Needs ◽

Glycine Modulatory Site ◽

Unmet Medical Needs

Schizophrenia is a severe mental illness that affects ~1% of the world's population. It is clinically characterized by positive, negative, and cognitive symptoms. Currently available antipsychotic medications are relatively ineffective in improving negative and cognitive deficits, which are related to a patient's functional outcomes and quality of life. Negative symptoms and cognitive deficits are unmet by the antipsychotic medications developed to date. In recent decades, compelling animal and clinical studies have supported the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia and have suggested some promising therapeutic agents. Notably, several NMDAR-enhancing agents, especially those that function through the glycine modulatory site (GMS) of NMDAR, cause significant reduction in psychotic and cognitive symptoms in patients with schizophrenia. Given that the NMDAR-mediated signaling pathway has been implicated in cognitive/social functions and that GMS is a potential therapeutic target for enhancing the activation of NMDARs, there is great interest in investigating the effects of direct and indirect GMS modulators and their therapeutic potential. In this review, we focus on describing preclinical and clinical studies of direct and indirect GMS modulators in the treatment of schizophrenia, including glycine, D-cycloserine, D-serine, glycine transporter 1 (GlyT1) inhibitors, and D-amino acid oxidase (DAO or DAAO) inhibitors. We highlight some of the most promising recently developed pharmacological compounds designed to either directly or indirectly target GMS and thus augment NMDAR function to treat the cognitive and negative symptoms of schizophrenia. Overall, the current findings suggest that indirectly targeting of GMS appears to be more beneficial and leads to less adverse effects than direct targeting of GMS to modulate NMDAR functions. Indirect GMS modulators, especially GlyT1 inhibitors and DAO inhibitors, open new avenues for the treatment of unmet medical needs for patients with schizophrenia.

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Treating schizophrenia with cariprazine: from clinical research to clinical practice. Real world experiences and recommendations from an International Panel

Annals of General Psychiatry ◽

10.1186/s12991-020-00305-3 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Andrea Fagiolini ◽

José Ángel Alcalá ◽

Thomas Aubel ◽

Wojciech Bienkiewicz ◽

Mats Magnus Knut Bogren ◽

...

Keyword(s):

Side Effects ◽

Real World ◽

Negative Symptoms ◽

Partial Agonist ◽

Term Treatment ◽

Positive Symptoms ◽

Drug Of Choice ◽

International Panel ◽

Long Term Treatment

Abstract Background Management of schizophrenia is sub-optimal in many patients. Targeting negative symptoms, among the most debilitating aspects of schizophrenia, together with positive symptoms, can result in significant functional benefits and dramatically improve quality of life for patients and their carers. Cariprazine, a partial agonist of the dopamine receptors D2/D3 has demonstrated effectiveness across symptom domains in clinical trials, particularly on negative symptoms. Objective To obtain a broader insight from clinicians with specific experience with cariprazine, on how it affects patient populations outside the clinical trial setting. Methods The panel addressed a series of psychopharmacologic topics not comprehensively addressed by the evidence-based literature, including characteristics of patients treated, dosing and switching strategies, duration of therapy, role of concomitant medications and tolerability as well as recommendations on how to individualize cariprazine treatment for patients with schizophrenia. Results Patients recommended for cariprazine treatment are those with first episodes of psychosis, predominant negative symptoms (maintenance/acute phase) and significant side effects (metabolic side effects, hyperprolactinemia, sedation) with other antipsychotics. When the long-term treatment of a lifetime illness is adequately weighted, cariprazine becomes one of the first-line medications, not only for patients with predominant negative symptoms but also for those with relatively severe positive symptoms, especially if they are at the first episodes and if a specific medication is added for symptoms such as agitation or insomnia. For instance, patients with agitation may also benefit from the combination of cariprazine and a benzodiazepine or another sedating agent. Cariprazine may be prescribed as add-on to medications such as clozapine, when that medication alone is ineffective for negative symptoms, and sometimes the first may be discontinued or its dose lowered, after a period of stability, leaving the patient on a better tolerated antipsychotic regimen. Conclusions Based on real-world clinical experience, the panel considered that cariprazine, with its distinct advantages including pharmacokinetics/pharmacodynamics, good efficacy and tolerability, represents a drug of choice in the long-term management of schizophrenia not only for patients with predominant negative symptoms but also for those with positive symptoms.

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