Has the utilization of serotonin receptor antagonism made an impact on schizophrenia treatment?

KEYWORDS:

• Atypical antipsychotics
• serotonin receptors
• serotonin and dopamine antagonists
• schizophrenia
• efficacy
• tolerability

1. Introduction

The introduction of atypical, i.e. second generation, antipsychotics (AAPs) since the discovery of clozapine, has been a big step in schizophrenia treatment. They are ‘atypical’ as their clinical profile differs from typical (first-generation) antipsychotics. All AAPs share dopamine and serotonin receptor antagonism (except for amisulpride, which preferentially binds to dopamine D2/D3 receptors). Besides antagonism to the dopamine D2 receptor, the AAPs also block other dopamine receptors such as D1, D3, or D4 [1]. The serotonergic system modulates a broad spectrum of the central nervous system functions through 5-HT binding to 5-HT receptors. The overwhelming majority of research has focused on 5-HT2A receptors antagonism. However, a variety of 5-HT receptors, such as 5-HT2A/2C, 5-HT1A, 5-HT3, 5-HT6, and 5-HT7 receptors, may contribute to the mechanisms of action of ‘atypicality’ [2]. For example, we have data indicating that 5-HT3 receptor antagonists (ondansentron) as adjunctive therapy can improve negative symptoms in schizophrenia [3]. Other molecular targets are also relevant for further AAPs characterization. Some AAPs act at adrenergic alpha 1/2, histamine (especially H1) and muscarinic receptors. Targeting glutamatergic neurotransmission may be also involved. Clinical characteristics of individual AAPs can be predicted according to their molecular profile [1].

The AAPs can be divided into four subgroups: firstly, compounds belonging to substituted benzamides that able to modulate dopaminergic neurons selectively and specifically. The first was sulpiride, which has been replaced in the clinic by amisulpride (synthesized 1978), a selective D2/D3 receptor antagonist. Secondly, a subgroup commonly called serotonin/dopamine antagonists. Risperidone (introduced in 1993), the first representative of this subgroup, has a relatively potent antagonism of 5- HT2A receptors and relatively weaker antagonism of D2 receptors. Risperidone shows also high affinity for alfa adrenergic receptors. Thirdly, a subgroup of AAPs called multi-target AAPs has also certain affinity for other receptors (histamine, muscarinic); this profile may explain their higher propensity for metabolic side effects. Among these, clozapine has a unique position as the first prototypic AAP. It was developed in 1961, followed by the second representative of this subgroup olanzapine much later (1996). Clozapine remains the most effective antipsychotic. Its effect is mediated not only through dopamine receptors but also serotonergic, noradrenergic, and glutamatergic receptors. In addition to its effect in treatment-resistant schizophrenia, clozapine has shown a decrease of suicidality and substance use in patients with schizophrenia.

Clozapine is also a suitable treatment option for psychoses associated with Parkinson diseases, and tardive dyskinesia [4]. Most recently, AAPs with novel dopamine D2/3 receptor partial agonist pharmacology have been advanced as ‘third-generation’ antipsychotics. Also, the mode of action of partial dopamine receptor agonists involves serotonin receptor antagonism as well.

These mechanisms allowed AAPs to bring significant relief to many patients not only in terms of hospitalization and reduction of symptoms severity but also in terms of safety [5].

The AAPs have become the drugs of choice not only in patients during their first psychotic break but they are also indicated for maintenance treatment. AAPs are prescribed also for affective disorders (depression and mania), and difficult-to-treat behavioral problems in geronto- and pedopsychiatry.

Historically, several lines of evidence support the hypothesis that serotonin system abnormalities play an important role in the pathogenesis and treatment of schizophrenia. The role of serotonin alterations in the pathophysiology of schizophrenia has long been suspected in view of the psychotogenic effects of serotonergic agonists and the therapeutic effects of 5 HT2 antagonists [2]. The current neurochemical hypothesis of schizophrenia is focusing on neurotransmitters (dopamine, serotonin, glutamate). The serotonin hypothesis attributes an important role to the hyperactivation of 5-HT2A receptors on glutamate neurons [5].

A close anatomical and functional relationship between 5-HT2A receptors and glutamatergic excitability supports the hypothesis that even 5-HT2A receptor antagonism alone could improve schizophrenia-like (psychotic) symptoms in disorders where dopaminergic antagonism is undesirable [6]. Following this idea, pimavanserin, a selective 5-HT2A receptor inverse agonist/antagonist with no dopaminergic activity, was approved by FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis [7].

2. Atypical antipsychotics in the treatment of schizophrenia

AAPs have been compared with typical, i.e. first-generation antipsychotics (TAPs) for overall efficacy, quality of life and tolerability, and most of them were in some aspects superior to TAPs [8]. Further, ¨there are differences among individual AAPs. Besides clozapine with its unique clinical effects, olanzapine, amisulpride, and risperidone demonstrated better outcomes than other APs [9,10]. AAPs cause fewer extrapyramidal side effects (EPS) at clinically optimal doses than TAPs, which are more likely to cause EPS.

On the other side the AAPS have higher propensity to induce metabolic side effects such as weight gain, dyslipidemia and glucometabolic disturbance. Of the AAPs, multi acting receptor targeted antipsychotics especially clozapine and olanzapine lead to substantially more metabolic side effects than other AAPs [11]. Two independently funded clinical trials with long follow-up (≥12 months), CATIE and CUtLASS, compared AAPs with TAPs in common clinical practice. The data from both trials indicated that efficacy was similar between the two groups and for side effects olanzapine was associated with significant metabolic side effects in comparison with the other tested antipsychotics [12].

2.1. New AAPs

Over the past decade, new oral AAPs (lurasidone, cariprazine, brexpiprazole) have become available. These new AAPs were developed with the aim of improving the efficacy in terms of negative, cognitive, and depressive symptoms as well as in terms of reducing metabolic side effects compared to prior AAPs, while keeping the risk of EPS low. However, studies directly comparing the effects of these new drugs with those of older AAPs are extremely rare [13].

Lurasidone is a representative of the serotonin and dopamine antagonist class. It is characterized by potent antagonism at the serotonin 5-HT7 receptor. Its unique pharmacological profile may be associated with a more pronounced improvement of some hard-to-influence schizophrenic symptoms, such as depression and cognitive dysfunction. This is supported by the improved efficacy of lurasidone compared to placebo in the treatment of depressive symptoms and cognitive dysfunction in comparison with quetiapine [14,15]. In terms of side effects, lurasidone was associated with a significantly lower weight gain but higher rates of akathisia, anxiety, and EPS compared to olanzapine and quetiapine. In a systematic review and meta-analysis of weight gains and metabolic side effects of AAPs, lurasidone was shown to be the treatment with the lowest increase in body weight (0.43 kg); in addition, it was also the only treatment associated with a decrease in total cholesterol and triglycerides and, furthermore, the highest decrease in HDL cholesterol [16].

Brexpiprazole and cariprazine (along with aripiprazole), belong to the D2/3 receptors partial agonists. The first representative of this subgroup, aripiprazole, was approved for use in schizophrenia treatment in the United States in 2002. The efficacy of this class of AAPs could be based on a simultaneous partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and binding affinity for 5-HT2A receptors [13].

Cariprazine, besides the above-mentioned profile, is a partial agonist of D3/D2 receptors with D3 preference. This property is unique to cariprazine. It acts as a partial agonist at the D2 and D3 receptors and 5-HT1A receptors. Partial agonists act either as a functional agonist or a functional antagonist, depending on the surrounding levels of naturally occurring dopamine (full agonist) [17]. This binding profile may be associated with pro-cognitive and antidepressant effects as well as the potential effect on negative symptoms of schizophrenia [18]. Cariprazine was better than risperidone in a large trial that was well controlled for secondary negative symptoms; it should be, however, noted that the trial was sponsored by its manufacturer [19]. Cariprazine is safe and well tolerated; common adverse events are EPS and akathisia with a dose-response relationship [13].

Brexpiprazole has equally high affinity for serotonin 5-HT1A, 2A and dopamine D2 receptors. It may improve cognitive dysfunction in schizophrenia as suggested by animal models; nevertheless, clinical trials are necessary to support that claim. Brexpiprazole is safe and well tolerated. Its lower intrinsic agonist activity at D2 receptors in comparison with aripiprazole may result in decrease of side effects mediated by dopamine D2 partial agonism, e.g. akathisia or restlessness, insomnia, and nausea [13]. Generally, the new AAPs are well tolerated regarding metabolic side effects (especially lurasidone) and hyperprolactinemia; however, frequency of akathisia remains still high with lurasidone and cariprazine.

3. Expert opinion

3.1. Current situation

Answer to the key question in the title is undoubtedly ‘yes.’ Serotonin receptor antagonism is an important mechanism where the efficacy and tolerability of antipsychotics are concerned. Emerging data on lumateperon and roluperidone indicate that serotonin receptor antagonism, specifically 5-HT2A receptor antagonism, may be a promising mechanism for attenuation of cognitive and negative symptoms. Lumateperone modulates simultaneously serotonin, dopamine, and glutamate, including the potent serotonin 5-HT2A receptor antagonism. Lumateperone is the latest addition to the family of AAPs approved for the treatment of acute schizophrenia (FDA, December 2018) [20]. Roluperidone, an antagonist at sigma-2 and 5-HT2A receptors, has progressed in phase 3 clinical testing, but results have not yet been published.

The relevance of serotonin receptors antagonism in the treatment of schizophrenia is also supported by results of genetic association studies. Besides genetic polymorphisms of CYP enzymes affecting pharmacokinetics, variability in pharmacodynamic genes (genes for serotonin receptors and/or transporters) has been associated with antipsychotic response and side effects such as weight gain [21].

AAPs are the fundamental biologic treatment for schizophrenia. They do not represent a homogenous group; each subcategory of this group has characteristic profiles on different molecular targets, associated with unique side effects profile and efficacy on schizophrenia symptoms. Under such situation, classification into TAPs and AAPs seems to be an oversimplification and the differentiation between typical and atypical antipsychotics starts to be a little obsolete. However, this classification is still widely used in clinical practice.

Schizophrenia is a complex syndrome involving interplay of genetic, epigenetic and environmental factors. The current phenomenological classification does not reflect the variety of mechanisms leading to psychopathology and patients are treated according to the diagnosis determined using this classification. When choosing a particular medication, the clinician should consider the unique pharmacological profile of each particular antipsychotic drug and the patient’s clinical characteristics.

For these reasons, a new system of classifying psychotropic drugs, Neuroscience-based Nomenclature (NbN) based on their pharmacological mechanisms, was proposed. It is continuously developing, revised, and complemented by new data [22].

3.2. Perspective

Nowadays, we are witnessing the beginning of a new era in medicine – precision medicine, which empowers the decision-making process using of measurable indicators of biological processes (biomarkers). We can expect that in the near future, psychiatry will make use of data obtained (especially) from genetic profiling, panomics, and structural and functional brain imaging for a new classification of psychiatric disorders based on psychobiological mechanisms of psychopathology, prediction of outcome, and treatment response, and development of new drugs. The search for the pathophysiological mechanisms underlying schizophrenia has indicated that trace-amine associated receptor-1 (TAAR1) presents a new target for treating schizophrenia. Ulotaront, a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity has moved to phase III clinical development for the treatment of schizophrenia [23]. Modulation of acetylcholinergic receptor represents a new treatment strategy. The promising results of early clinical trials with drugs targeting nicotinic systems have not been confirmed.

Cholinergic drugs acting at M1/M4 muscarinic receptors appear to have greater potential for improving schizophrenia symptoms. In a phase 2 clinical trial, a combination of the muscarinic receptor agonist xanomeline and the anticholinergic agent trospium demonstrated significant antipsychotic efficacy [24].

Finally, continuous efforts for understanding the underlying neurobiology appear to be the most promising path to developing fundamentally new methods of treatment for psychiatric illnesses. Implementation of precision psychiatry into clinical practice has the potential to become a tool for personalized treatment in the true sense of the word.

Disclosure of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed they have been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of or received honoraria from talks and/or consultancy of: Adamed, Angelini, Casen-Recordati, Exeltis, Ferrer, Janssen, Lundbeck, Neuraxpharm, Otsuka, Pfizer and Sanofi, and received grants from the Spanish Ministry of Health. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.