Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole

Abstract

Background:

Brexpiprazole and cariprazine are the latest US Food and Drug Administration approved atypical antipsychotics available in the United States. Both function as partial agonists of the dopamine-2 receptor (D₂R), a mechanism of action shared with aripiprazole. However, all three differ in their affinities for the D₂R as well as for serotonin receptors (5-HTRs). This paper seeks to delineate these pharmacodynamic and clinical differences amongst the three dopamine partial agonist atypical antipsychotic drugs.

Methods:

PubMed and clinicaltrials.gov searches were used to generate preclinical and clinical evidence for review. Data derived from animal models and human subjects were used to provide insight on clinical mechanisms and adverse effect potentials. Clinical trial data were reviewed to compare clinical efficacy and adverse effects.

Results:

Efficacies among the three drugs are comparable for their shared indications. Side-effect profile and underlying pharmacodynamic mechanism of action for each drug may differ.

Conclusion:

Partial agonism of the D₂R is a similarity of the three drugs reviewed. Each drug varies in affinity for both the D₂R and a diverse group of 5-HTRs, generating a distinct profile of clinical indications and adverse effects for each.

Keywords

brexpiprazole cariprazine aripirazole antipsychotic dopamine partial agonist

Introduction

In the mid-twentieth century, typical antipsychotics, heralded by the ‘anti-histamine’ chlorpromazine, relieved patients of psychotic symptoms, but at the cost of frequent extrapyramidal symptoms (EPS), tardive dyskinesia (TD), and hyperprolactinemia. In the early 1990s, risperidone, the first of a class of newer, atypical antipsychotics, reduced the frequency of these effects, due chiefly to antagonism of the 2A serotonin receptor (5-HT_2AR). Antagonizing 5-HT_2AR leads indirectly to downstream effects that raise dopamine neurotransmission in EPS-prone brain areas (e.g. nigrostriatal system). For example, typical antipsychotic-induced shortages of dopamine activity along the nigrostriatal pathway may lead to Parkinsonism, dystonia, akathisia, or neuroleptic malignant syndrome. Simultaneously, lower dopamine transmission in the mesolimbic circuits alleviates psychosis. The typical antipsychotics were not selective as they provided both efficacy and higher rates of EPS. To lower EPS, the check and balance selectivity provided by 5-HT_2AR antagonism allows greater dopamine activity to remain within the nigrostriatal pathway while preferentially lowering psychotic symptoms theoretically by preferentially dampening the mesolimbic pathway. The advantage of atypical antipsychotics is a match in efficacy with the typical antipsychotics but allowing for much fewer EPS [Stahl, 2013]. This accomplishment led to obsolescence for many of the older typical antipsychotics, shifting their use downward along most guideline algorithms [Lehman et al. 2004].

Within a decade of the emergence of the first novel atypical risperidone, aripiprazole introduced yet another novel mechanism. Perhaps more atypical than its counterparts, aripiprazole is a partial agonist of the D₂R. Until 2015, it was the only available agent within the class of atypical antipsychotics that could both stimulate and inhibit dopamine at the moment it engaged the D₂R. At high DA concentrations, aripiprazole lowers DA neuronal firing, while at low concentrations it increases DA firing. At the time, this mechanism of action was called ‘dopamine stabilization’ because a single drug could increase or decrease neuronal firing as needed. The newly approved brexpiprazole and cariprazine also utilize this D₂ partial agonism mechanism.

The partial agonist effect is interesting in that it allows an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D₂R. The goal of this intermediate level is to remain beneath the threshold development of positive symptoms induced by excessive dopamine, but not too low, ideally to avoid adverse effects such as EPS [Stahl, 2013].

Comparative approved indications

Aripiprazole has been approved for schizophrenia in both adults and adolescents; acute bipolar mania as either monotherapy or as an adjunctive therapy to lithium or valproate for both adults and pediatric patients; maintenance treatment for bipolar I disorder in adults; major depressive disorder in adults as adjunctive therapy to antidepressants; irritability associated with autism spectrum disorder in pediatric patients; Tourette’s disorder in pediatric patients; and via intramuscular injection for agitation associated with schizophrenia or bipolar mania in adults as well as long-acting injectable depot forms for schizophrenia [Alkermes, 2015; Otsuka, 2014, 2015a].

Brexpiprazole has received approval for treating major depressive disorder in adults as an adjunctive therapy to antidepressants; and to treat schizophrenia in adults [Otsuka, 2015b].

Cariprazine is approved for treating acute mania or mixed episodes associated with bipolar I disorder in adults; and for treating schizophrenia in adults [Actavis, 2015]. A recent study demonstrated the efficacy of cariprazine in alleviating certain negative symptoms of schizophrenia as well [Debelle et al. 2015]. Table 1 Summarizes the FDA approved indications for these three drugs.

Table 1.

US Food and Drug Administration approved indications for aripiprazole, brexpiprazole, and cariprazine [Actavis, 2015; Alkermes, 2015; Otsuka, 2014, 2015a, 2015b].

	Aripiprazole	Brexpiprazole	Cariprazine
Schizophrenia (adults)	✓	✓	✓
Schizophrenia (adolescents)	✓
Schizophrenia or bipolar mania associated agitation (adults) via intramuscular route	✓
Schizophrenia depot injection	✓
Bipolar disorder (adults and pediatric patients), acute monotherapy for mania	✓
Bipolar disorder (adults and pediatric patients), acute adjunctive treatment to lithium or valproate for mania	✓
Bipolar disorder (adults only), acute treatment of manic or mixed episodes	✓		✓
Bipolar disorder (adults only), maintenance treatment	✓
Adjunctive treatment of major depressive disorder (adults)	✓	✓
Tourette’s disorder (pediatric patients)	✓
Irritability associated with autistic spectrum disorder (pediatric patients)	✓

Comparative pharmacodynamic mechanisms

All three drugs interact with the following receptors: partial agonism of D₂R, the dopamine-3 receptor (D₃R), and the serotonin-1A receptor (5-HT_1AR); and antagonism of the serotonin receptors 2A, 2C, and 7 (5-HT_2AR, 5-HT_2CR, 5-HT₇R, respectively), the histamine-1 receptor, (H₁R), the muscarinic-1 cholinergic receptor (M₁R), and the α1 adrenergic receptor (α₁R) [Stahl, 2013]. Theoretically, each of these interactions may allow for symptomatic efficacy or clinical side effects to occur.

For D₂R partial agonism, brexpiprazole has the strongest affinity followed by aripiprazole and cariprazine [Actavis, 2015; Otsuka, 2014, 2015b]. Regarding D₃R partial agonism, cariprazine has the strongest affinity followed by aripiprazole and brexpiprazole [Actavis, 2015; Otsuka, 2014, 2015b]. In high DA areas of the brain, D₃R partial agonism has the net effect of dampening DA neuronal firing, thus lowering psychosis or mania. Theoretically, higher affinity should yield stronger clinical effects. There may also be an association with increased cortical static tone for alertness and wakefulness if the D₃R is agonized. Evidence amassed so far includes statistically and clinically significant improvements in positive symptoms of schizophrenia among subjects found to possess DRD3 polymorphisms for the D₃R gene, and this D₃ property may be implicated as a risk to developing schizophrenia symptoms [Adams et al. 2008]. Animal models have demonstrated that negative symptoms improve, including cognition and social behavior, with D₃R agonism [Gross, 2012]. Cariprazine, in particular, is distinguished from the other two drugs in its predilection for and relative strength in binding the D₃R [Kiss et al. 2010]. Cariprazine selectively binds the D₃R at comparatively lower doses. As such, this suggests that D₃R partial agonism in the cortex may improve dopaminergic function and thus help improve negative symptoms of schizophrenia or the vegetative symptoms of depression.

Interestingly, there are more serotonin receptors being manipulated by these atypical agents compared with dopamine receptor modulation. In regard to 5-HT_1AR partial agonism, brexpiprazole has the strongest affinity followed by aripiprazole and cariprazine [Actavis, 2015; Otsuka, 2014, 2015b]. Partial agonism of the 5-HT_1AR may increase dopamine release in the mesocortical pathway, similar to the partial agonism of D₃R. Therefore, partial agonism of either D₃R or 5-HT_1AR may account for antidepressant effects. This mechanism is utilized by the psychotropics buspirone, vilazodone, and vortioxetine. For 5-HT_2AR antagonism, brexpiprazole has the greatest affinity followed by aripiprazole and cariprazine [Actavis, 2015; Otsuka, 2014, 2015b]. In this case, it is antagonism that ultimately allows greater amounts of DA to act with in the nigrostriatal system, thus lowering EPS. For 5-HT_2CR antagonism, aripiprazole has the strongest affinity followed by brexpiprazole and cariprazine [Actavis, 2015; Otsuka, 2014, 2015b]. Concerning 5-HT₇R antagonism, brexpiprazole has the strongest affinity followed by aripiprazole and cariprazine [Actavis, 2015; Otsuka, 2014, 2015b]. Antagonism of the 5-HT_2CR and the 5-HT₇R are both thought to provide antidepressant activity [Stahl, 2013]. 5-HT_2C blockade likely increases frontocortical NE and DA similar to the antidepressant mirtazapine [Gobert et al. 2000]. 5-HT₇R antagonism likely improves cognition and circadian function as noticed in the antidepressant effects of vortioxetine and lurasidone [Hedlund et al. 2005].

The above properties may enhance clinical effectiveness. The next properties may yield side effects. Analysis of H₁R antagonism suggests that brexpiprazole has the strongest affinity followed by cariprazine and aripiprazole [Actavis, 2015; Otsuka, 2014, 2015b]. Antihistaminergic side effects include sedation and weight gain (sometimes associated with the cardiometabolic sequelae of atypical antipsychotics). Less antagonism of the H₁R means fewer antihistaminergic effects. Aripiprazole is the drug with the weakest affinity, suggesting a tolerability advantage here. M₁R antagonism (all three drugs show extremely weak affinity and therefore little antagonism) may cause anticholinergic effects, including impaired accommodation (cycloplegia), increased intraocular pressure, xerostomia, constipation, tachycardia and urinary retention. For α₁R antagonism, brexpiprazole has the strongest affinity followed by aripiprazole and cariprazine [Actavis, 2015; Otsuka, 2014, 2015b]. Again, cariprazine, with the weakest affinity is expected to have the least antagonism and theoretically the lowest rate of anti-α₁R effects, which include sedation and hypotension. Interestingly, high affinity here may have an advantage if treating patients who have nightmares, akin to the effect of the α₁R antagonist prazosin.

In summary, and based upon official US Food and Drug Administration (FDA) values as found in package inserts, the binding affinities, K_i (nM), of these receptors are summarized in Table 2 [Actavis, 2015; Otsuka, 2014, 2015b]:

Table 2.

Binding affinities of aripiprazole, brexpiprazole, cariprazine, and the clinical properties of the receptors.

	Aripiprazole	Brexpiprazole	Cariprazine	Therapeutic effects	Adverse effects
D₂	0.34	0.30	0.49	Antipsychotic	EPS, tardive dyskinesia, akathesia, NMS hyperprolactinemia
D₃	0.8	1.1	0.085	Antipsychotic (including negative symptoms), antimanic, antidepressant
5-HT_1A	1.7	0.12	2.6	Antidepressant, anxiolytic
5-HT_2A	3.4	0.47	18.8	Anti-EPS
5-HT_2C	15	34	134	Antidepressant
5-HT₇	29	3.7	111	Antidepressant
H₁	61	19	23.2	Anxiolytic, anti-insomnia	Weight gain sedation
M₁	>1000	>1000	>1000	Opposes EPS	Xerostomia, constipation, blurry vision, cognitive dysfunction, falls (e.g. older adults)
α₁	57	3.8	155	Antihypertensive	Sedation, orthostasis

Comparing the three partial D₂ agonists:

(1) Aripiprazole has the greatest affinity for 5-HT_2CR; it has the weakest affinity for H₁R. Theoretically, this suggests it may be less associated with metabolic symptoms and perhaps elevate monoamines for better antidepressant effects, therapeutically speaking. It may be the least sedating.

(2) Brexpiprazole shows the greatest affinity for D₂R, 5-HT_1AR, 5-HT_2AR, 5-HT₇R, H₁R, and α₁R; it has the weakest affinity for D₃R. This suggests the possibility that it can both inhibit and enhance dopamine activity to a higher degree, treating either psychosis or depression. The serotonin modulation is highly suggestive of antidepressant activity.

(3) Cariprazine shows the greatest affinity for D₃R; it is the weakest in affinity for D₂R, 5-HT_1AR, 5-HT_2AR, 5-HT₇R, and α₁R. This may promote a fair amount of dopamine activity and act as an antidepressant. The serotonin modulation is highly suggestive of antidepressant activity.

EPS, extrapyramidal symptoms; NMS, neuroleptic malignant syndrome.

Comparative pharmacokinetics and dosing

Aripiprazole’s chemical structure is shown in Figure 1. Initial dosage varies with the indication. The lower initial dose of 2 mg/day is used for schizophrenia in adolescents, bipolar mania in pediatric patients, adjunct treatment for depression (2–5 mg), irritability associated with autism, and for Tourette’s disorder. The intramuscular injection is initially 9.75 mg for agitation associated with either schizophrenia or bipolar mania in adults; if the oral route is used instead, then initial dosage starts at 10–15 mg/day. Recommended therapeutic doses range from 5 mg (Tourette’s disorder, irritability associated with autism, and major depression adjunctive treatment) to 15 mg (bipolar mania and schizophrenia in adults) per day, with maximum daily doses ranging from 10 mg (Tourette’s disorder) up to 30 mg (bipolar mania and schizophrenia among all ages). Tablets are available in doses of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg; orally disintegrating tablets of 10 and 15 mg, oral solution of 1 mg/ml, and injection of 9.75 mg/1.3 ml [Otsuka, 2014]. Depot form is available in 300 or 400 mg lyophilized powder, dosed monthly, and 441, 662, or 882 mg single-use prefilled syringes for aripiprazole lauroxil either monthly or every 6 weeks (882 mg only) [Otsuka, 2015a; Alkermes, 2015]. Oral doses are taken once daily without requiring food. Injections for acute agitation require 2 h between administrations. Metabolism is via hepatic Cytochrome (CYP) P4503A4 (CYP3A4) and 2D6. Known CYP2D6 poor metabolizers or those concurrently taking strong CYP2D6 inhibiters should take half the usual dose and a quarter dose if a strong inhibitor of CYP-3A4 is coprescribed; coadministration of a strong CYP3A4 inducer calls for a doubling of the usual aripiprazole dose. Steady state is achieved in 14–15 days, when the pharmacokinetics is dose proportional. The half life is 75 h for the parent compound and 94 h for its major metabolite, dehydroaripiprazole, which shows similar affinity for D2 receptors. Oral bioavailability is 87% [Alkermes, 2015; Otsuka, 2014, 2015a].

Brexpiprazole’s chemical structure is shown in Figure 2. The initial dose for schizophrenia is 1 mg/day, with a recommended dose of 2–4 mg/day with 4 mg/day as the maximum daily dose (3 mg/day if there is comorbid moderate-to-severe hepatic or renal impairment). The starting dose for major depression is 0.5–1 mg/day up to a recommended 2 mg/day; maximum dose is 3 mg/day (unless moderate or severe renal or hepatic impairment, when the maximum dose is 2 mg/day). Tablets are available in 0.25, 0.5, 1, 2, 3, and 4 mg. Metabolism is mediated by CYP3A4 and CYP2D6. Known CYP2D6 poor metabolizers or those taking a drug with strong inhibition of CYP2D6 and CYP3A4 are instructed to take half the usual dose similar to aripiprazole; if both criteria are met, then the dose is quartered. CYP3A4-inducing drugs taken concurrently should double the dose over 1 or 2 weeks. Oral bioavailability is 95%. The half life of brexpiprazole is 91 h, with steady-state level reached by 10–19 days, which is longer than that of aripiprazole. Administration requires no food. When highly protein bound (>99%), brexpiprazole did not affect warfarin, diazepam, or digoxin dosing [Otsuka, 2015b].

Cariprazine’s chemical structure is shown in Figure 3. The starting dose is 1.5 mg/day for both schizophrenia and bipolar mania. The recommended dose is between 1.5 and 6 mg/day for schizophrenia and 3–6 mg/day for bipolar mania. Capsules are available in doses of 1.5 mg, 3 mg, 4.5 mg, and 6 mg. Cariprazine is metabolized by CYP3A4 and those also taking a CYP3A4 strong inhibitor are instructed to take half the usual dose of cariprazine. Unlike the previous two drugs, this drug is not a 2D6 substrate. The drug is highly protein bound (97%). The reported half life is a range of 2–4 days, which is either shorter or more prolonged than aripiprazole’s 75 h half life for the parent compound. However, cariprazine’s active metabolite, didesmethyl, is longer lasting with a half life between 1 and 3 weeks. Peak plasma concentrations of cariprazine are achieved in 3–6 h. Cariprazine’s steady state is 10–20 days [Actavis, 2015].

In summary, the longest half life, if its active metabolite is included, is cariprazine’s, which is as long as 3 weeks (a range of 1–3 weeks); aripiprazole and brexpiprazole follow with 94 and 91 h, respectively. If only the parent compound is considered, then cariprazine, with as long as 4 days (2–4-day range), still has the longest half life, but this time aripiprazole has the shortest half life with 75 h, with brexpiprazole at 91 h. Consequently, cariprazine’s range (parent compound) suggests that it could be either the longest or the shortest of the three, while it is clearly the longest lasting given the active metabolite.

Collectively, this subclass of atypical antipsychotics have the longest-ranging half lives.

Clinical studies

Aripiprazole

Schizophrenia

Four trials all gave rise to statistically significant changes in scores using the Positive and Negative Syndrome Scale (PANSS) [Cutler et al. 2006; Findling et al. 2008; Kane et al. 2002; McEvoy et al. 2007; Potkin et al. 2003]. A 4-week trial reduced the PANSS score by nearly 16 at 15 mg/day and 11 at 30 mg/day [Kane et al. 2002]. This was greater than placebo by approximately 13 and 9 points, respectively [Kane et al. 2002]. A second study, comparing 20 and 30 mg strengths, reduced the score by 15 and 14 points, with improvements over placebo of 10 and 9, respectively [Potkin et al. 2003]. The third, comparing the various strengths evaluated in the previously described studies, revealed changes for 10, 15, and 20 mg/day of 15, 12, and 14, respectively, improvements of 13, 9 and 12 compared with placebo, respectively [McEvoy et al. 2007]. In a fourth study, lower strength dosages were included, with 2, 5, and 10 mg, yielding reductions of 8, 11, and 11, or 3, 5, and 5 compared with placebo, respectively [Cutler et al. 2006]. Additionally, a 6-week study of younger patients treated with 10 and 30 mg/day lowered the PANSS score by 27 and 29 or 6 and 7, respectively, compared with placebo, yielding FDA approval for use in patients from the age of 13 [Findling et al. 2008].

Bipolar disorder

For the acute treatment of manic and mixed episodes associated with bipolar disorder, the Young Mania Rating Scale (YMRS) was the primary endpoint. Aripiprazole was assessed in four studies with dosages between 15 and 30 mg [Keck et al. 2003, 2009; Sachs et al. 2006; Young et al. 2009]. The first study, with 15 mg/day, yielded reductions of 13 (an improvement of 5 over placebo) [Sachs et al. 2006]. The second study yielded decreases of 8 (5 compared with placebo) [Keck et al. 2003]. The third study, a reduction in score of 13, or 4-point greater reduction than placebo [Keck et al. 2009]. The fourth study led to a reduction of 12, a decrease of 2 more than Young and colleagues [Young et al. 2009]. A separate study for pediatric patients used 10 and 30 mg strengths and after 4 weeks yielded reductions of 14 and 15, or differences from placebo of 6 and 7, respectively [Findling et al. 2013]. As adjunctive treatment in bipolar disorder, aripiprazole or placebo was given to patients already taking lithium or valproate at therapeutic levels but who were not clinically responding after 2 weeks; reductions of 13, a difference of 3 over placebo resulted, resulted with statistical significance [Vieta et al. 2008].

Major depressive disorder

To assess efficacy as adjunctive treatment of major depressive disorder, subjects who had initially been tested and confirmed as treatment resistant to either selective-serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) alone were randomized to receive either an adjunctive placebo or adjunctive aripiprazole, at strengths between 2 and 20 mg/day [Marcus et al. 2008]. The primary endpoint was the change, over 6 weeks, in the Montgomery–Asberg Depression Rating Scale (MADRS). Adjunctive aripiprazole resulted in a MADRS score reduction of 8, compared with 6 for placebo [Marcus et al. 2008]. A second study, also 6 weeks in duration and allowing up to 20 mg, reduced the MADRS score by 9 versus the placebo’s 6 [Berman et al. 2007].

Autism spectrum disorder

Aripiprazole gained approval to treat irritability associated with autism spectrum disorder. Using the Aberrant Behavior Checklist’s (ABC) subscale for irritability, improvements over an 8-week period were assessed in two studies between those receiving aripiprazole and placebo [Marcus et al. 2009; Owen et al. 2009]. The primary efficacy outcome was mean change in score. In the first study, with subjects receiving between 2 and 15 mg/day, by week eight there was a reduction by 13 for aripiprazole versus 5 for placebo [Owen et al. 2009]. The second study stratified according to dosages of 5, 10, and 15 mg, all resulted in significant ABC score reductions of 12, 13, and 14 compared with an average placebo reduction of 8 [Marcus et al. 2009].

Tourette’s disorder

For treating young patients with Tourette’s disorder, two trials assessed as primary outcomes decreases in the Yale Global Tic Severity Score [Otsuka, 2015c; Yoo et al. 2013]. In the first study, starting at 2 mg, patients under 50 kg ultimately received low dose aripiprazole of 5 mg and those over 50 kg a higher target dose of 20 mg; over 8 weeks, both low- and high-dose aripiprazole achieved statistical significance, approximately doubling the reduction in Total Tic Score (TTS) compared with placebo [Otsuka, 2015c]. The second study, over 10 weeks, also started at 2 mg but allowed for all subjects to titrate up to 20 mg. The result was a statistically significant five-point reduction in the TTS [Yoo et al. 2013].

Acute agitation in schizophrenia or bipolar mania

For acute intramuscular injection for agitation associated with either schizophrenia or bipolar mania, the primary efficacy measure compared values of PANSS (the primary efficacy measure) at baseline versus 2 h post injection. A secondary endpoint was Clinical Global Impressions Severity scale (CGI-S). Two trials employed haloperidol as comparator [Andrezine et al. 2006; Tran-Johnson et al. 2007]. The first trial compared four different strengths (1, 5.25, 9.75, and 15 mg), while the second trial studied 9.75 mg alone. With the exception of 1 mg strength, the trials yielded statistically significant results on both PANSS (reductions of 6 and 7, respectively) and CGI-S [Andrezine et al. 2006; Tran-Johnson et al. 2007]. A third trial devoted to bipolar disorder associated agitation, using instead lorazepam as comparator, studied strengths of 9.75 and 15 mg, yielding statistically significant results, a reduction of 9 compared with placebo [Zimbroff et al. 2007].

Long-acting injectable for schizophrenia

The first aripiprazole depot preparation to receive FDA approval involved a 12-week trial comparing once-monthly 400 mg injections with placebo using the PANSS, which resulted in a greater improvement in score over placebo of 15 [Kane et al. 2014]. In a longer term trial (52 weeks), the primary measure of efficacy was time to exacerbation of psychotic symptoms/impending relapse [Kane et al. 2012]. Aripiprazole’s time to relapse was significantly greater than for placebo. Further, scores on the PANSS and CGI-S were significantly improved for those given aripiprazole compared with placebo [Kane et al. 2012].

Aripiprazole lauroxil, another long-acting injectable preparation, was studied over 12 weeks in adults with schizophrenia receiving either 441 or 882 mg, or placebo once monthly [Meltzer et al. 2015]. Statistically significant decreases in the primary efficacy measure, the PANSS, were reached with both 441 and 882 mg, by approximately 11 and 12, respectively. Both dosages also achieved statistically significant results (either ‘much improved’ or ‘very much improved’) on the CGI Improvement (CGI-I) scale. Further, all these results were considered clinically meaningful in reducing psychotic symptoms both in response to an acute exacerbation and maintained over the following 12 weeks [Meltzer et al. 2015].

Brexpiprazole

Schizophrenia

Leslie Citrome devoted a systematic review entirely to brexpiprazole [Citrome, 2015]. The author outlines two phase III studies which found statistically significant reductions compared with placebo, based again on the PANSS score for the therapeutic dosages of 2 and 4 mg in one study, and 4 mg in the other [Correll et al. 2015; Kane et al. 2015]. In the first study, 2 and 4 mg improved PANSS scores compared with placebo by 9 and 8, respectively [Correll et al. 2015]. The second study found success with 4 mg and a 6-point greater reduction of PANSS score [Kane et al. 2015].

Major depressive disorder

For efficacy in controlling major depressive disorder as an augmentation strategy, a pair of 6-week, double-blinded, placebo-controlled studies compared changes in MADRS [Thase et al. 2015a, 2015b]. The subjects had previously been treated over 8 weeks with a standard antidepressant, and those not responding were then randomized and augmented with brexpiprazole or placebo. Treatment response was based on a reduction of at least 50% in MADRS score. The first study evaluated 1 and 3 mg strengths, and only the 3 mg strength improved MADRS compared with placebo with statistical significance [Thase et al. 2015a]. The second study used 2 mg, which improved MADRS by three more than placebo (p = 0.0002) [Thase et al. 2015b].

Cariprazine

Schizophrenia

Cariprazine gained FDA approval following statistically significant differences in PANSS scores compared with placebo in three, 6-week trials [Durgam et al. 2014, 2015a, 2015b]. One employed risperidone as an active control while studying 1.5, 3, and 4.5 mg strengths, with improvements over placebo of 8, 9, and 10, respectively [Durgam et al. 2014]. A second study instead used aripiprazole as active control for 3 mg cariprazine (with an improvement of 6 over placebo) and 6 mg (better by 9 over placebo) [Durgam et al. 2015a]. A third study used two flexible-dose range groups of 3–6 mg and 6–9 mg, both showing superiority to placebo with least squares mean differences of 7 for the 3–6 mg dose range and 10 for the 6–9 mg range [Durgam et al. 2015b].

Bipolar mania

For efficacy treating bipolar mania, three, 3-week placebo-controlled, double-blinded trials used the YMRS [Calabrese et al. 2015; Durgam et al. 2015c; Sachs et al. 2015]. All demonstrated efficacy with doses starting at 3 mg/day. The first study used two flexible-dose range groups of 3–6 and 6–12 mg/day, each resulting in greater scores than placebo by 6 [Calabrese et al. 2015]. A second and a third study both used dose ranges of 3–12 mg/day, with improvements over placebo of 6 and 4, respectively [Durgam et al. 2015c; Sachs et al. 2015]. Within this effective range of 3–12 mg/day, strengths higher than 6 mg were not superior to lower doses, especially given associations between dose and adverse effects [Calabrese et al. 2015; Durgam et al. 2015c; Sachs et al. 2015].

Comparative efficacy

Citrome also recently compared aripiprazole, brexpiprazole, and cariprazine using number needed to treat (NNT) statistical analysis [Citrome, 2005]. His extended work features a table that concisely compares efficacy, particularly including 95% confidence intervals of the statistically significant improvements of these three drugs over placebo. Among schizophrenia trials, aripiprazole resulted in the greatest reduction in PANSS (by 12.7 to brexpiprazole’s 8.7 and cariprazine’s 10.4); for bipolar mania, cariprazine reduced YMRS the most (6.1 to aripiprazole’s 5.3); and for adjunctive treatment for major depression, brexpiprazole showed the greatest reduction in MADRS (3.2 to aripiprazole’s 3.0) [Citrome, 2005]. However, the confidence intervals overlap between drugs for the same indication and scale, which is suggestive of comparable efficacy based on the results of these trials [Citrome, 2005]. While there are no current, three-way novel head-to-head comparative trials, differences found across trials suggest comparative efficacy owing to no statistical significance. Per FDA standards, it seems that if each antipsychotic is dosed appropriately it can lower psychosis in schizophrenia. There are no current data for cariprazine in treating depressive disorder so brexpiprazole and aripiprazole have a distinct advantage. For treating mania, brexpiprazole has minimal data, and both aripiprazole and cariprazine have garnered regulatory approval.

Comparative adverse effects

Aripiprazole

Tables 3 –8 list the adverse effects for each agent. The most common adverse effects for aripiprazole were headache (27%), agitation (19%), anxiety (17%), insomnia (16%), akathisia (13%), nausea (13%), vomiting (11%), constipation (10%), dyspepsia (9%), and dizziness (9%).

Table 3.

Constitutional adverse effects.

	Aripiprazole	Brexpiprazole	Cariprazine
Fatigue	6% (4%)	3% (2%)	3% (1%)
Decreased appetite	–	–	3% (1%)
Increased appetite	3% (1%)	3 (2%)	–
Pyrexia	–	–	1% (1%)
Weight increase	–	5% (2%)	2% (1%)

Placebo rates appear in parentheses.

Table 4.

Cardiovascular effects.

	Aripiprazole	Brexpiprazole	Cariprazine
Hypertension	–	–	4% (1%)
Tachycardia	6% (3%)	–	2% (1%)
orthostasis	4% (3%)	–	–

Placebo rates appear in parentheses.

Table 5.

Dermatologic effects.

	Aripiprazole	Brexpiprazole	Cariprazine
Rash	7% (7%)	–	4% (1%)

Placebo rates appear in parentheses.

Table 6.

Gastrointestinal effects.

	Aripiprazole	Brexpiprazole	Cariprazine
Abdominal discomfort/pain	3% (2%)	–	5% (5%)
Constipation	10% (6%)	2% (1%)	8% (5%)
Diarrhea	7% (8%)	3% (2%)	4% (3%)
Dry mouth	5% (4%)	–	2% (2%)
Dyspepsia	9% (7%)	3% (2%)	6% (5%)
Elevated AST/ALT		–	1% (0%)
Nausea	13% (9%)	4% (4%)	8% (6%)
Oropharyngeal pain	–	–	2% (2%)
Toothache/dentalgia	4% (3%)	–	3% (3%)
Vomiting	11% (6%)	–	6% (4%)

Placebo rates appear in parentheses.

ALT, alanine transaminase; AST, aspartate transaminase.

Table 7.

Neurological effects.

	Aripiprazole	Brexpiprazole	cariprazine
Blurry vision	3% (1%)	–	3% (1%)
Dizziness	9% (6%)	3% (1%)	5% (3%)
Extrapyramidal disorders (w/o akathisia)	4% (2%)	6% (3%)	21% (10%)
Akathisia	13% (4%)	7% (3%)	14% (4%)
Dystonia	1% (0%)	–	3% (0%)
Parkinsonism	4% (0%)	–	18% (8%)
Tremor	5% (3%)	3% (2%)	–*
Headache	27% (21%)	9% (9%)	12% (13%)
Inattention	3% (1%)	–	–
Sedation	7% (4%)	5% (1%)	–^$
Somnolence	5% (3%)	3% (2%)	7% (5%)

Placebo rates appear in parentheses.

Tremor was considered a component of Parkinsonism in the cariprazine studies.

Sedation was considered a component of somnolence in the cariprazine studies.

Table 8.

Psychiatric effects.

	Aripiprazole	Brexpiprazole	Cariprazine
Agitation	19% (17%)	8% (9%)	–
Anxiety	17% (13%)	2% (1%)	–
Insomnia	16% (10%)	8% (7%)	8% (7%)
Restlessness	5% (3%)	2% (0%)	5% (3%)

Placebo rates appear in parentheses.

Aripiprazole showed the highest rates of the three drugs for fatigue, increased appetite (tied with brexpiprazole), tachycardia, xerostomia, constipation, nausea and vomiting, blurry vision (tied with cariprazine), dizziness, headache, agitation, anxiety, insomnia, and restlessness (tied with cariprazine).

Aripiprazole showed the lowest rate of the three drugs for EPS (excluding akathisia), dystonia, Parkinsonism, and abdominal pain.

Brexpiprazole

For brexpiprazole, the 10 most common adverse effects were headache (9%), agitation (8%), insomnia (8%), akathisia (7%), EPS excluding akathisia (6%), sedation (5%), weight increase (5%), and nausea (4%). Many of these effects are reduced compared with aripiprazole. Notably, akathisia is almost 50% less.

Interestingly, brexpiprazole showed the highest rate of the three drugs for increased appetite (tied with aripiprazole), and weight increase.

Brexpiprazole showed the lowest rate of the three drugs for akathisia, fatigue (tied with cariprazine), constipation, diarrhea, dyspepsia, nausea, dizziness, headache, and somnolence.

Cariprazine

Cariprazine’s most common adverse reactions included EPS excluding akathisia (21%), Parkinsonism (18%), akathisia (14%), insomnia (8%), constipation (8%), nausea (8%), somnolence (7%), dyspepsia (6%), and vomiting (6%). Compared with the previous two agents, cariprazine may have the greatest EPS risk.

Cariprazine showed the highest rate of the three drugs for EPS (excluding akathisia), Parkinsonism, akathisia, abdominal pain, somnolence, and restlessness.

Cariprazine showed the lowest rate of the three drugs for fatigue (tied with brexpiprazole), weight gain, tachycardia, xerostomia, vomiting, and insomnia (tied with brexpiprazole).

Discontinuation rates due to adverse effects are shown in Table 9. Cariprazine had the highest rate, followed by aripiprazole, and then brexpiprazole with the lowest rate. The most common adverse effect leading to discontinuation for all three atypicals was akathisia. Among the placebo group, the most common adverse effects were either worsening psychotic or manic symptoms, presumably due to nontreatment.

Table 9.

Discontinuation rates due to adverse effects.

	Aripiprazole	Brexpiprazole	Cariprazine
Discontinuation rates	8.8% (7.5%)	5.7% (5.0%)	10.1% (9.4%)

Placebo rates appear in parentheses.

Discussion

This paper has sought to thoroughly review a subclass of second-generation antipsychotics that may be referred to collectively as dopamine stabilizers or dopamine-2/3 receptor partial agonists. All agents when faced with neurophysiologic dopamine neuronal hyperactivity in the limbic system act as net dopamine antagonists and slow limbic firing, and all diminish psychosis in schizophrenia equally. All can facilitate dopamine activity in the limbic system or cortex if physiologically dopamine activity is below normal. This likely is a procognitive, drive and energy mechanism, and theoretically could enhance antidepressant response. Aripiprazole and brexpiprazole are approved in the area for depression management and cariprazine is currently being investigated. For a patient with concurrent depression and psychosis, the selection between aripiprazole and brexpiprazole may be based on the different adverse effect profiles, given their comparable efficacies; the rate of insomnia for brexpiprazole was half that of aripiprazole, for example, which could guide therapy for a patient already deprived of sleep. Cariprazine has recently gained regulatory language, suggesting it can improve negative schizophrenia symptoms which would be a first in class. It is possible that certain negative symptoms can be extrapolated to those experiencing depressive disorder (amotivation, apathy, lack of will or drive, etc.) and this drug may be used off label for depression and ideally will gain regulatory approval.

Additionally, all three agents manipulate a variety of serotonin receptors. The SSRI Plus class of antidepressants has been recently heralded by the approval of vilazodone and vortioxetine, which tout a basic SSRI property plus serotonin 1a receptor partial agonism (vilazodone/vortioxetine) and 3/7 receptor (vortioxetine) antagonism. This latter drug has gained regulatory language, stating it may improve cognition in people with depression. This is drawing awareness to specific serotonin receptor modulation in the antidepressant class, but many of the properties are found in the three dopamine-stabilizing atypical antipsychotics discussed here. They all may have antidepressant effects that are also steeped in procognitive and procircadian mechanisms. These are truly multimodal drugs that have gained disease state indications and approvals for use but pharmacodynamically may be theoretically helpful in improving agitation, aggression, anxiety, insomnia, fatigue, attention, and concentration regardless of disease state. Future clinical studies are warranted in these areas.

The authors suggest using these drugs front line within their approved areas. If an initial agent is fraught with side effects, then switching to one of the other three is clearly warranted as side-effect profiles are subtly different as sedation, weight gain, and akathisia rates differ. Clinicians may choose the drug based on side-effect profile. This approach dates back to the 1950s–1990s and may be comparable to choosing a high- versus low-potency first-generation typical antipsychotic. Per class labeling all three of these agents carry warnings for EPS, TD, metabolic disorder, increased suicidality in young adults being treated for depressive disorder, agranulocytosis, and risk of stroke or cardiac death in those with dementia. Informed consent and diligent clinical monitoring is warranted. Off-label use should be documented, with clinical rationale and perhaps comment about pharmacodynamic theory being used to guide the choice of drug in the absence of defined clinical trials in the off-label disease state area. Finally, if there is a therapeutic failure despite adequate dosing of one of these three agents, any of the other agents may be tried as they all have a subtly unique pharmacodynamic receptor affinity profile that may offer an advantage to patients on a case-by-case basis.

Footnotes

Acknowledgements

This paper is the sole work of the authors.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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