Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Ankara, Turkey
Received Date: June 14, 2016; Accepted Date: June 22, 2016; Published Date: June 27, 2016
Citation: Canan KUS (2016) Novel Antipsychotic Drugs Approved in 2015: Brexpiprazole, Cariprazine, Aripiprazole Lauroxil. Med chem (Los Angeles) 6:425-428. doi:10.4172/2161-0444.1000380
Copyright: © 2016 Canan KUS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Medicinal Chemistry
Antipsychotic agents, highly benefit for the treatment of a range of psychiatric disorders and act by blocking dopamine receptors in the brain and interfering with dopaminergic transmission. Schizophrenia and mania which are psychosis are treated by antipsychotic drugs. These medicines are classified as typical or atypical antipsychotic drugs. The recently developed drugs which are named 'atypical antipsychotics' are useful in patients that do not respond to treatment with other typical antipsychotics. This review puts emphasis on the recent progress in therapeutically attractive piperazine derivatives being novel atypical antipsychotics that were apporved in 2015. Differences in safety-tolerability, affected receptors, activity, side effects are displayed in this review.
Antipsychotic; Brexpiprazole; Cariprazine; Aripiprazole lauroxil
This review consists of novel antipsychotics that approved in 2015, brexpiprazole, cariprazine, and aripiprazole lauroxil. All of the compounds are piperazine derivatives, their affects, affected receptors, and adverse effects are just about same. Differences in safetytolerability, affected receptors, activity, side effects are displayed in this review (Table 1).
|Antipsychotic Agent||Brexpiprazole||Cariprazine||Aripiprazole lauroxil|
|Date of approval||2015 July||2015 September||2015 October|
|Chemical Structure||phenyl piperazine||phenyl piperazine||phenyl piperazine|
|Classification||atypical antipsychotic, Second generation||atypical antipsychotic, Second generation||atypical antipsychotic, Second generation|
|Affected receptor||Serotonin-dopamine activity modulator, partial agonist at 5-HT1A and dopamine D2 receptors, and antagonist at 5-HT2A and noradrenaline α1B and α2C receptors, all at similar potency||Dopamine D2 parcial agonist
agonism at 5-HT1A
D3-preferring D3/D2-receptor partial agonist
|Dopamine D3/D2 parcial agonist
Parcial agonism at 5-HT1A
|Usage for||Schizophrenia, major depressive disorder||Schizophrenia, bipolar disorder||Acute schizophrenia bipolar disorder schizophrenia, bipolar disorder|
gastrointestinal side effects,
moderate weight gain,
increases in serum CPK
agitation, distress restlessness
weight gain, agitation, distress, and restlessness
Leukopenia, Neutropenia, and Agranulocytosis
| neuroleptic malignant syndrome
high blood sugar
Uncontrolled movements of the face and body
drooling and tremors
agitation or anxiety, insomnia,
|Recommended oral dose||2-4 mg/day in schizophrenia, 2-3 mg/day in major depression||an oral capsule available in 4 dosage strengths: 1.5 mg, 3 mg, 4.5 mg, and 6 mg.||every four to six weeks
every 6 weeks for the 882 mg dose
as an injection
Table 1: Novel antipsychotics.
All antipsychotic medications in current clinical use act primarily on the dopamine system (most are D2 antagonists) and are only efficacious for positive symptoms with little efficacy for all eviating the negative or cognitive symptoms . They act by blocking dopamine receptors in the brain and interfering with dopaminergic transmission and they are used to treat psychosis, including schizophrenia and mania .
Schizophrenia is a psychiatric disorder that affects approximately 0.4% of individuals in the adult population worldwide that significantly impedes on normal vocational and social functioning [3-5]. Evidence for this disorder was first reported in humans as deficits in prepulse inhibition (PPI=Percentage pre-pulse inhibition) of the startle response, which serves as an operational measure of sensorimotor gating [6,7].
Schizophrenia is characterized by a constellation of signs and symptoms. It is aheterogeneous clinical syndrome, with no single symptom being pathognmonic of the disorder. Despite it being almost 100 years since  seminal description of dementia prae-cox, effective management of all of the symptoms of schizophreni are mains elusive.
Neuroleptic treatment can cause numerous side effects, including the often irreversible movement disorder tardive dyskinesia except for aripiprazole (they are rare) . Many of the therapeutic actions and side effects of antipsychotics can take days to weeks, and in some cases months, to develop . Because of that, basic research has turned increasingly toward an investigation of the effects of chronic neuroleptic treatment on neuronal systems. In addition, most second-generation antipsychotics are antagonists of serotonin 5-HT2A receptors and α-1- adrenoreceptors, and individual compounds have a variety of effects on other monoamine receptors, such as 5-HT1A receptors. These broad target effects have the objective of either improving antipsychotic efficacy (with additional effects on affective symptoms or cognitive deficits) or mitigating adverse effects like, extrapyramidal symptoms (EPS) [11,12].
If the D2 intrinsic activity is too high, this can lead to lack of robust antipsychotic activity as well as pronounced adverse effects related to increased D2 receptor tonus, like, nausea, vomiting, and motor side effects, such as hyperkinesias and restlessness [13-15], where as D2 antagonist activity leads to an increased risk of EPS and increased prolactin secretion . Akathisia (the movement disorder) is another common side effect associated with dopamine receptor antagonists, and may be associated with subjective distress in patients .
Antipsychotics are classified both typical/atypical and first/second generation. Atypical antipsychotics are the recently developed drugs that are useful in patients that do not respond to treatment with other typical antipsychotics. Atypical antipsychotics have a pharmacological profile different from typical antipsychotic drugs that being primer generation. They cause less extrapyramidal side effects compared to the older typical antipsychotic drugs. Atypicals are more effective in treatment-resistant patients and have a greater efficacy to treat negative symptoms than typical antipsychotics .
Atypical second generation antipsychotics (SGAs) appear to have broadly similar efficacy as FGAs against the manic symptoms of bipolar disorder, but there are important differences in their tolerability profiles, which are likely to be of particular relevance during long-term treatment . Almost all have received regulatory approval for use in mania, including aripiprazole .
Brexpiprazole, cariprazine, aripiprazole lauroxil are novel atypical antipsychotics. Aripiprazole, approved by the United States Food and Drug Administration in 2002, appears to have fewer metabolic adverse effects than other atypical antipsychotics , by the way, aripiprazole lauroxil is approved in 2015. So far, aripiprazole is the only one D2 partial agonist, with moderate D2 intrinsic activity, has reached the market , whereas other compounds with higher D2 intrinsic activity are in development  or have been discontinued during development, often because of lack of sufficient clinical efficacy, like, bifeprunox .
Brexpiprazole is a novel serotonin dopamine activity modulator. It combines 5-HT1A receptor partial agonism and low-intrinsic activity D2 receptor partial agonism with antagonist activity on a variety of 5-HT and a-adrenergic receptors. The main focus of this article is the receptors that are most influenced by brexpiprazole at clinically and pharmacologically relevant plasma exposures. The pharmacological effects of brexpiprazole in test models of positive symptoms of schizophrenia and of cognitive impairment [25,26].
For brexpiprazole, the most common treatment-emergent adverse events were headache, insomnia and agitation; incidences of akathisia were lower in the brexpiprazole treatment groups (4.2%-6.5%) versus placebo (7.1%). There were no clinically relevant changes in laboratory parameters and vital signs. Brexpiprazole 4 mg is an efficacious and well-tolerated treatment for acute schizophrenia in adults .
For Cariprazine, the most commonly encountered adverse events in the mania trials were extrapyramidal disorder, akathisia, insomnia, vomiting, restlessness, sedation, vision blurred, and akathisia, extrapyramidal disorder, tremor, dyspepsia, vomiting, dizziness, diarrhea, and somnolence.
Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late-stage clinical development for the treatment of schizophrenia, as well as for bipolar disorder (manic/mixed and depressive episodes), and as an adjunctive agent for the treatment of major depressive disorder .
Cariprazine differs from aripiprazole in terms of dopamine D3 receptor selectivity. In short-term, randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. In the fixeddose study of cariprazine that tested 1.5, 3.0, and 4.5 mg/day, the most commonly encountered adverse events were insomnia, extrapyramidal disorder, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation. However, the differences in incidence versus placebo for these events were generally small .
Although aripiprazole has offered a new approach to stabilizing the dopaminergic system, an improvement could potentially be made by developing a novel compound that maintains significant partial agonist activity at D2 receptors, but with lower intrinsic activity. In addition to the issue of optimal D2 intrinsic activity, optimization of the pharmacological profile by a combination of additional target effects is a well known strategy to improve the clinical efficacy and tolerability of antipsychotics.
Aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) are two different long-acting injectable formulations of aripiprazole. AL is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths, also led to approval of dosing intervals of every 6 weeks for the 882 mg dose .
Side effects of aristada (aripiprazole lauroxil): Akathisia, contraindication Cerebrovascular Adverse Reactions (Including Stroke), Neuroleptik Malignant Syndrome, Tardive Dyskinesia, metabolic changes, hyperglycemia / diabetes mellitus, dyslipidemia, weight gain, orthostatic hypotension, leukopenia, neutropenia, agranulocytosis, seizures, potential for Cognitive and Motor Impairment, difficulties with body temperature regulation, dysphagia, Injection-Site Reactions (rash, swelling, redness, irritation at the point of injection), distonia and pregnancy and nursing complications .
Fountoulakis and Vieta published that aripiprazole appears effective for the treatment and prophylaxis against mania. The data on bipolar depression are so far negative; however there is a need for further study at lower dosages. The most frequent adverse effects are extrapyramidal signs and symptoms, especially akathisia, without any significant weight gain, hyperprolactinaemia or laboratory test changes .
On October 5, the U.S. Food and Drug Administration approved Aristada extended release injection to treat adults with schizophrenia. Aristada is administered by a health care professional every four to six weeks using an injection in the arm or buttocks. The efficacy of Aristada was demonstrated in part by a 12-week clinical trial in 622 participants. In participants with acute schizophrenia who had been stabilized with oral aripiprazole, Aristada was found to maintain the treatment effect compared to a placebo.
Aristada and other atypical antipsychotic drugs used to treat schizophrenia have a Boxed Warning alerting health care professionals about an increased risk of death associated with the off-label use of these drugs to treat behavioral problems in older people with dementiarelated psychosis. No drug in this class is approved to treat patients with dementia-related psychosis. Aristada must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks .
Most atypical antipsychotics more fully block dopamine receptors in the brain, while aripiprazole only partially blocks the activity of these receptors.
The role of serotonin in depression has also been well documented, and the affinity of atypical antipsychotics for the serotonin transporter as well as post-synaptic serotonin receptors suggests a role for this neurotransmitter . Brexpiprazole has potent activity at the serotonin 5HT1A (partial agonist) and noradrenergic alpha-1 and alpha-2 (antagonist) receptors . It exhibits moderate antagonist activity at the serotonin 5HT7 and 5HT2C and histamine H1 receptors and negligible activity at the muscarinic cholinergic M1 receptor.
Brexpiprazole displayed almost equal subnanomolar affinities for several cloned human receptors, including h5-HT1A, hD2L, and 5-hHT2A receptors, as well as hα1B- and hα2C-adrenoceptors. Although both brexpiprazole and aripiprazole showed high affinities for h-5HT1A and hD2 receptors, brexpiprazole had a slightly higher affinity for h5- HT1A receptors than hD2 receptors, whereas the reverse was true for aripiprazole. Furthermore, brexpiprazole bound with about ten times higher affinity to h5-HT1A and h5-HT2A receptors and much higher affinity to hα1B- and hα2C-adrenoceptors than aripiprazole. The consequences of the high affinities of brexpiprazole for (and antagonist effects on) α1B- and α2C-adrenoceptors are more difficult to predict because of a lack of selective compounds for studying the functional importance of these receptors .
Although both brexpiprazole and aripiprazole showed high affinities for h-5HT1A and hD2 receptors, brexpiprazole had a slightly higher affinity for h5-HT1A receptors than hD2 receptors, whereas the reverse was true for aripiprazole [25,26].
In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist and antagonist-related adverse effects. Brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders .
Cariprazine has more moderate affinity for human 5-HT1A receptors (Ki 3 nM) and acts as a partial agonist at this receptor. Affinity at other receptors is weaker. This includes human 5-HT2A (Ki 19 nM), histamine H1 (Ki 23 nM), 5-HT7 (111 nM), and 5-HT2C (134 nM) receptors. Low affinity was observed for all tested adrenergic receptors .
There is a lack of understanding of the pharmacological mode of action of most psychoactive drugs. Many have similar 3D structures so that it is not easy to rationalize their differing relative potency in different clinical settings. However, significantly SAR for different degrees of internal mobility suggests that molecular dynamics should be an additional factor considered when trying to understand the mode of action of this clinically important family of molecules .
All of the novel antipsychotics (brexpiprazole, cariprazine, aripiprazole lauroxil) are pheylpiperazine derivatives. At the same time, they are partial agonist at the dopamine D2 receptor.
It is apparent that the molecules, pathways, and systems thought to be involved in anxiety and depression are interconnected. The pharmacological profiles of psychoactive drugs are complex and, since they interact with many receptor sites, they often result in numerous side effects. Because of the side effects, more selective antipsychotic are needed.
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals