The Treatment of Adult Bipolar Disorder with Aripiprazole: A Systematic Review

Bipolar disorder is characterized by exacerbations of opposite mood polarity, ranging from manic to major depressive episodes. In the current nosological system of the Diagnostic and Statistical Manual – 5th edition (DSM-5), it is conceptualized as a spectrum disorder consisting of bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, and bipolar disorder not otherwise specified. Treatment of all phases of this disorder is primarily with mood stabilizers, but many patients either show resistance to the conventional mood stabilizing medications or are intolerant to their side-effects. In this setting, second-generation antipsychotics have gained prominence as many bipolar subjects who are otherwise treatment refractory show response to these agents. Aripiprazole is a novel antipsychotic initially approved for the treatment of schizophrenia but soon found to be effective in bipolar disorder. This drug is well studied, as randomized controlled trials have been conducted in various phases of bipolar disorders. Aripiprazole exhibits the pharmacodynamic properties of partial agonism, functional selectivity, and serotonin-dopamine activity modulation – the new exemplars in the treatment of major psychiatric disorders. It is the first among a new series of psychotropic medications, which now also include brexpiprazole and cariprazine. The current review summarizes the data from controlled trials regarding the efficacy and safety of aripiprazole in adult bipolar patients. On the basis of this evidence, aripiprazole is found to be efficacious in the treatment and prophylaxis of manic and mixed episodes but has no effectiveness in acute and recurrent bipolar depression.


Introduction And Background
Bipolar disorder (BD) is a common neuropsychiatric condition with a prevalence rate of approximately 4% in the general population, considering the entire bipolar spectrum [1]. It is characterized by severe disturbances in the mood of opposite polarity, which range from mania to depression. It is a chronic condition with the usual onset in adolescence or early adulthood and affects males and females equally [2]. It is highly comorbid with other diseases, such as anxiety spectrum disorders, substance abuse disorders, eating disorders, stressor-related disorders, and certain personality disorders, chiefly borderline personality disorder [3]. It can be complicated by severe depressive exacerbations, mixed episodes, rapid cycling, and subthreshold symptoms and is associated with one of the highest suicide rates among all psychiatric disorders [4]. Even after adequate treatment with currently available agents, affective episodes often fail to remit completely with persistence of symptoms and accompanying myriad complications in the biopsychosocial domain.
In this event, there is an unmet need for medications that are truly effective in different phases of the disorder. Unlike conventional mood stabilizers and older antipsychotics, secondgeneration antipsychotics (SGA) are multifunctional as these have shown efficacy in a broad range of psychiatric disturbances, including manic, depressive, and maintenance phases of bipolar disorder [5]. SGAs are exemplified by medications, such as risperidone, olanzapine, quetiapine, ziprasidone, and lurasidone, which are widely employed in the treatment of BD [6]. In addition to these, a new group of agents, the prototype of which is aripiprazole, is also available. The armamentarium of medications in this regard has increased with the United States Food and Drug Administration (FDA) approval of brexpiprazole and cariprazine. These are related compounds, and Figure 1 gives their chemical structures for the sake of comparison. These novel agents have been variously termed "third generation antipsychotics" or "serotonin-dopamine activity modulators" and are gaining prominence in the treatment of major psychiatric ailments, such as BD, major depressive disorder (MDD), and schizophrenia. There are subtle but important differences in the mechanism of action of SGAs and novel antipsychotics. Whereas the former act as full antagonists or inverse agonists at the dopamine D2 receptor (D2R), the latter behave as partial agonists at this site [7]. They may have disparate activity in different areas of the brain, depending on the prevalent dopaminergic tone, and act as full antagonists in regions with high dopamine neurotransmission but as partial agonists where this trend is low [8]. Presumably, this dual action has a putative mitigating effect on positive psychotic symptoms by virtue of the dopamine-blocking action in the mesolimbic area, whereas there is alleviation of negative and cognitive symptoms because of the facilitation of dopamine transmission in the prefrontal cortex [9]. Further, novel antipsychotics purportedly act as biased ligands at the D2R, which is a G-protein-coupled receptor (GPCR). This implies that they differentially stimulate intraneuronal signal transduction pathways, in contradistinction to other antipsychotics, which do not discriminate with downstream signaling cascades. This phenomenon has been termed "functional selectivity" and may have key connotations in the treatment of main psychiatric conditions by novel antipsychotics [10].
In the case of BD, repeated affective episodes have been shown to cause neuroinflammation, oxidative, and nitrosative stress leading to increased apoptosis of neurons in the hippocampus and other key mood-regulating areas of the brain. Administration of psychotropic drugs, like the novel antipsychotics, is neuroprotective with dendritic growth, increased synaptogenesis, and enhanced viability of neurons [11]. With the continued use of these medications, the deteriorating course of BD, a fundamentally neuroprogressive condition, is halted and is clinically manifested as longer periods of euthymia and improved psychosocial functioning of the patients.
Aripiprazole, the forerunner of the novel antipsychotics, has been well studied in different phases of BD. This review presents a comprehensive appraisal of the extant literature, focusing on randomized controlled trials (RCT). This endeavor illuminates the role of aripiprazole in the treatment of adults with BD, a difficult to treat condition, which manifests in innumerable ways and is often refractory to the currently available psychotropic agents.

Review Search strategy
A search of the PubMed database was conducted in October 2015 with the inclusive term "aripiprazole and bipolar." A total of 490 items were found which included reviews, case reports, pharmacokinetic investigations, clinical and preclinical studies. Narrowing the search to "clinical trials" retrieved 61 items and further refinement with "adults" resulted in 48 studies. The titles and abstracts of these papers were examined for relevance to the current topic, leading to exclusion of a further 25 studies. The rationale was to leave out records that had their main focus on other medications or psychiatric conditions. The resulting 23 studies were read in full and their reference lists consulted. Data from these papers was used to mark out the place of aripiprazole in the treatment of adults with bipolar disorder. Figure 2 illustrates the study selection process according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Table 1 lists the studies included in the systematic review.

FIGURE 2: Flow diagram of the systematic review
Selection of the studies according to the PRISMA statement. PRISMA -Preferred Reporting Items for Systematic Reviews and Meta-analyses.

Pharmacokinetic Data
The drug is available in oral form and in an intramuscular formulation for acute administration for the rapid control of agitated psychotic behavior. More recently, a long-acting injectable composition has been approved by the FDA for the maintenance treatment of schizophrenia. The orally taken drug is well absorbed with a bioavailability of 87% and can be used without regards to ingestion of food. It shows linear pharmacokinetics at therapeutic doses with peak plasma concentrations reached between three to five hours after intake. Aripiprazole has a long half-life of approximately 75 hours so that patients can still maintain therapeutic blood levels even if they forget to take it in the short term [12]. Steady state plasma levels are achieved after about 14 days of continuous administration. It is extensively metabolized in the liver by cytochrome P450 (CYP) 2D6 and 3A4 isoenzymes. The former is responsible for dehydrogenation and hydroxylation and the latter for dealkylation of the drug. Dehydroaripiprazole is the active metabolite of the drug and has an even longer half-life of 96 hours. Aripiprazole does not induce or inhibit CYP450 enzymes and, therefore, causes no interference with the elimination of other medications. However, subjects who are deficient in CYP2D6 (8% of Caucasians) have about a 60% higher blood concentration of aripiprazole, and in such individuals, the half-life of the compound approximately doubles [13]. The selective serotonin reuptake inhibitor, paroxetine, is a strong inhibitor of CYP2D6 and greatly reduces the hepatic clearance of aripiprazole. Likewise, inducers (e.g., carbamazepine) or inhibitors (e.g., fluvoxamine) of CYP3A4, respectively, decrease or increase serum aripiprazole levels.

Pharmacodynamic Data -Dopamine D2 Receptor Binding
Aripiprazole is a partial agonist at dopamine D2R; it has a high affinity for this site and, at therapeutic doses, occupies approximately 95% of D2R in the striatum. However, it shows low intrinsic activity at this receptor and causes much lower activation of the D2R compared to the endogenous ligand, dopamine [14]. The key notion put forward is that it acts as a full antagonist at D2R when the synaptic concentration of dopamine is high and as a partial agonist when this value is low. Taking together its high affinity and partial agonism at D2R, it supposedly antagonizes the burst firing of dopaminergic neurons, explaining its therapeutic effects; at the same time, it allows tonic activity of this neurotransmitter, resulting in a low incidence of extrapyramidal side effects (EPSE). The consequence of this mechanism may be an overall reduction in dopamine activity in the mesolimbic region of the brain while there is a maintenance of stimulant effect in the mesocortical and nigrostriatal areas [15].

Functional Selectivity/Biased Ligand Pharmacology
D2R is a G-protein-coupled receptor, and ligand binding results in downstream signaling via inhibition of adenyl cyclase. However, experiments in rodents have shown that D2R-mediated effects can occur independently of this mechanism through the scaffolding protein, β-arrestin 2. The latter associates with protein kinase B (Akt) and protein phosphatase 2A, causing activation of glycogen synthase kinase-3 (GSK-3); β-arrestin 2/Akt/GSK-3 signaling is implicated in major psychiatric disorders, including BD and schizophrenia [16]. Drugs like aripiprazole can have a differential effect on GPCR and, acting as a biased ligand, can discerningly activate one or the other pathway depending on receptor conformation. The supposed functional selectivity at GPCR by agents like aripiprazole, brexpiprazole, and cariprazine have given novel perspective to the treatment of hitherto intractable mental conditions and will undoubtedly be a principal focus for the development of better and more effective psychotropic medications [17]. Figure 3 schematically illustrates key concepts in this pharmacodynamic model.

FIGURE 3: Purported mechanism of biased signaling by novel antipsychotics
Biased ligands are presumed to act in a functionally discriminating manner at G-proteincoupled receptors, e.g. D2-type. One method of functional selectivity may be the favored binding to diverse conformations of the receptor, activating different downstream pathways according to the local milieu and the neuronal subtypes in which these are expressed. Postsynaptic scaffolding proteins, adaptors, and effectors may be discrepantly affected by each receptor conformation-related cascade differentially stimulated by the ligand.

Other Receptor Interactions of Aripiprazole
In several in vitro experiments, aripiprazole has performed as a partial agonist at 5HT1A receptors, whereas other data suggest that it acts as an agonist at the somatodendritic 5HT1A autoreceptors found in the dorsal raphe serotonergic neurons. The latter has major projections to the prefrontal cortex and decreased serotonergic firing mediated by the activation of 5HT1A autoreceptors, in turn, causes an increase in the dopaminergic tone. Working through this mechanism, aripiprazole may improve cognitive and negative symptoms in bipolar spectrum disorders and schizophrenia. In this vein, brexpiprazole and aripiprazole have been more aptly described as "serotonin-dopamine activity modulators" [18]. Further, aripiprazole has been shown to act as an agonist at 5HT2C receptors and this action has been regarded as advantageous in decreasing appetite and avoiding antipsychotic-induced weight gain. 5HT2A antagonism is a property that aripiprazole shares with other SGAs and the ramifications of this interaction embrace a reduction in EPSE during therapy with these agents. Finally, it only moderately blocks the alpha 1 adrenergic and histamine H1 receptors, which may account for the low incidence of orthostatic hypotension and sedation with the use of this compound.

Extrapyramidal Side Effects
Apparently because of aripiprazole's low intrinsic activity and partial agonism at D2R, there is a sustained stimulating effect of the endogenous ligand, dopamine, in the nigrostriatal pathway accounting for fewer EPSE with its use. The most commonly reported adverse events are akathisia and tremor while the rest of the EPSE-like dystonias, pseudo-parkinsonism, and tardive dyskinesias are conspicuously uncommon. When EPSE occur, these are generally of mild to moderate nature, translating into a low discontinuation rate for aripiprazole because of these side-effects.

Metabolic Effects
Bipolar disorder is viewed as a systemic illness with such manifestations as obesity, serum lipid abnormalities, and diabetes. Many atypical antipsychotics have the liability to cause or aggravate the metabolic syndrome, which is marked by increased body mass index, dyslipidemia, and glucose intolerance. According to a comprehensive literature review, among the SGAs, clozapine, olanzapine, quetiapine, and risperidone emerge as the worst offenders, whereas aripiprazole appears to have the fewest adverse metabolic effects [24]. The safety of aripiprazole in bipolar subjects is borne out by a post-hoc analysis of a 26-week study, which shows rates of metabolic syndrome with aripiprazole comparable to placebo [25]. According to the data from controlled short and long-term studies, there are no significant negative effects of aripiprazole mono or adjunctive therapy on such parameters as serum cholesterol, triglycerides, or glucose.

Effect on Prolactin Secretion
The discharge of dopamine from the hypothalamus is a signal for the anterior pituitary gland to prohibit the release of prolactin, and antipsychotics, which strongly bind to D2 receptors like haloperidol and risperidone, let go of this control by acting as antagonists. Contrarily, aripiprazole, a partial agonist at the D2R, appears to facilitate dopamine transmission in the tuberoinfundibular pathway and prevents hyperprolactinemia from occurring. Raised serum prolactin is associated with such untoward effects as sexual dysfunction, amenorrhea, galactorrhea, and bone demineralization. There is evidence that aripiprazole therapy may perhaps be associated with an overall decline in the serum prolactin level in bipolar patients who switch from other antipsychotics to this medication [26].

Effect on Electrocardiogram (ECG)
Some psychotropic medications, including antipsychotics such as thioridazine and ziprasidone, are associated with prolongation of the corrected QT (QTc) interval, which can potentially lead to such lethal arrhythmias as torsades de pointes. As far as aripiprazole is concerned, evidence from studies in bipolar patients shows that it has no such untoward effect and does not cause QTc prolongation [26].

Acute Manic Phase Studies
The efficacy of aripiprazole monotherapy in the treatment of acute mania has been studied in at least four RCTs. According to the existing literature, the most recent study was a multicenter, double-blind trial of Japanese patients, which investigated the efficacy and safety of aripiprazole ( [27]. These results were in line with two earlier key trials of aripiprazole, 30 mg, versus placebo conducted mainly in Caucasian populations [19][20]. In an RCT, Bipolar I patients with acute manic or mixed episodes were randomized to two fixed doses of aripiprazole (15 or 30 mg/d) or placebo. In this three-week trial, both of the active agent groups were not statistically better than placebo on the primary efficacy measure of YMRS at endpoint [28].
In a well-powered trial, both aripiprazole and haloperidol showed a significantly greater mean change in the YMRS compared to placebo at Week 3 with equivalent improvements for the two medications at Week 12 [29]. In another study evaluating aripiprazole, lithium, and placebo for three and 12-week periods, aripiprazole showed significant improvement in the mean YMRS score within two days. This improvement carried on over three weeks and was sustained over 12 weeks in an analogous manner for both drugs [30]. In another trial, more acutely manic patients were in remission and taking aripiprazole compared to haloperidol at the study endpoint at Week 12 [31]. In summary, in these trials, which compared aripiprazole (doses of 15-30 mg) to established standard antimanic treatments, there was an equivalent efficacy of the active agents. Additionally, using YMRS scores as the benchmark, corresponding early and continued separation from placebo was noted and remission rates were achieved at three and 12 weeks, with the advantage of proportionately lower drop-outs in subjects taking aripiprazole.
In an RCT, aripiprazole showed additional benefits adjunctive to lithium or valproate in acute manic and mixed episodes. Bipolar I patients with acute mania partially nonresponsive to the mood stabilizer alone and receiving combined treatment with aripiprazole and one of the mood stabilizers demonstrated a significantly higher reduction of their baseline YMRS score at Week 6 versus placebo (at study endpoint: -13.3 for aripiprazole, -10.7 for placebo). In this trial, similar to the monotherapy studies, significant improvement in YMRS total score was noted with aripiprazole versus placebo from Week 1 onward [21]. In a study, both adjunctive aripiprazole and haloperidol with the first-line mood stabilizer, divalproex sodium, were equally efficacious in acute bipolar mania; the novel antipsychotic was associated with fewer EPSE as compared to haloperidol but caused greater weight gain and sedation [32]. In subjects aged 10 to 17 years and presenting with acute manic or mixed episodes, aripiprazole monotherapy was statistically superior to placebo in inducing remission, was well-tolerated, and did not result in any significant weight gain [33]. A post-hoc analysis of two short-term, three-week monotherapy trials of subjects with BD Type I experiencing acute manic or mixed episodes is instrumental in elucidating the efficacy of this medication across a wide range of illness characteristics associated with treatment resistance. The data was stratified according to the severity of manic symptoms, the presence of depressive features, psychosis, and history of rapid cycling. The salutary effects of aripiprazole therapy were seen in these different subsets of cases with severe disease attributes, epitomizing that this agent has an important place in the treatment of bipolar diathesis [34]. Finally, while this article was in revision, a published meta-analysis showed that in both controlled and real-world settings, aripiprazole was superior to placebo and equal to active comparators in acute and stabilization phases of bipolar mania. Its safety profile was similar to other antipsychotics when considering such side effects as sedation, akathisia, EPSE, and weight gain but had a notably lower tendency to cause hyperprolactinemia [35].
The data presented above is further explained in Table 2. 2016   The safety and efficacy of aripiprazole have been studied in RCTs in the continuation phase following treatment of acute manic or mixed episodes in Bipolar I disorder. In a placebocontrolled monotherapy trial, hospitalized bipolar patients with manic or mixed episodes were initially given open-label aripiprazole (15 or 30 mg/d). Those who achieved sustained remission (YMRS ≤ 10; MADRS ≤ 13) for at least six weeks were assigned to either placebo or aripiprazole in a double blind way and followed for the total study duration of 26 weeks. It was determined that the active treatment (both doses) was statistically significant compared to placebo in delaying time to manic, but not depressive, relapse and was relatively well tolerated with a low incidence of side effects [36].
A 52-week trial evaluated the safety and efficacy of aripiprazole + lithium or valproate versus placebo + lithium or valproate in manic subjects who had an inadequate response to mood stabilizer monotherapy during at least two weeks of treatment. Aripiprazole was added in a non-double blind mode and those patients who became stable for 12 consecutive weeks (YMRS and MADRS scores ≤ 12) were randomized to the active drug or placebo and followed in a double-blind manner for a total of 52 weeks. The results showed that, evaluated against the placebo, significantly more patients who responded to add-on aripiprazole in the acute manic or mixed phase remained relapse-free with the active drug during the continuation phase. This finding suggested that there was a long-term benefit in continuing aripiprazole adjunctive to the first-line mood stabilizers for relapse prevention of manic and mixed episodes, once sustained remission was achieved with the combination regimen in Bipolar I disorder patients [22]. A post-hoc analysis of a 52-week double-blind, placebo-controlled trial of adjunctive aripiprazole and first-line mood stabilizers in Bipolar I patients with initial manic or mixed episodes showed that this agent was more effective in preventing relapses in those with index manic, as compared to mixed episodes [37].
In a 52-week study, completers of a six-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania who were only partially responsive to previous lithium or valproate monotherapy could enter a 46-week extension with open-label aripiprazole + lithium or aripiprazole + valproate. Using the last observation carried forward to account for drop-outs, it was noticed that statistically significant improvement from baseline over the 52 weeks occurred with aripiprazole + lithium/valproate on the mean YMRS and Montgomery-Asberg Depression Rating Scale (MADRS) total scores. In summary, this openlabel study demonstrated that long-term aripiprazole in conjunction with traditional mood stabilizers was efficacious in the prophylaxis of manic or mixed episodes, maintained the functioning of bipolar patients, and had a good safety and tolerability profile [38]. A continuation phase RCT in Korean patients could not replicate these findings. In this 24-week study, adjunctive aripiprazole and lithium or valproate were not statistically better than placebo + mood stabilizer in preventing affective recurrences [39]. In a long-term trial, aripiprazole + lamotrigine was not significantly superior to placebo + lamotrigine in delaying time to affective relapse in Bipolar I patients [40].
Lastly, in a long-term 52-week study, aripiprazole and lithium were analyzed head-to-head in a double-blind manner. In the stabilization phase, Bipolar I disorder subjects with initial manic or mixed episodes were treated double-blind with the above-mentioned medications for 12 weeks. Those who achieved sustained remission (YMRS and MADRS scores ≤ 12), were followed in the same manner for a further period of 40 weeks. Statistics were drawn on observed cases only, and although there was a high attrition rate, the completers of the study had equivalent benefit in the prevention of manic and mixed episodes. In contrast to lithium, data showed that aripiprazole was better tolerated with fewer and less severe adverse events [41].

Maintenance Study in Patients with Initial Manic or Mixed Episode
A 100-week aripiprazole monotherapy study was conducted in a placebo-controlled, doubleblind style to assess the safety and efficacy of the drug in preventing relapse of mood episodes in Bipolar I disorder patients. Bipolar subjects with a recent manic or mixed episode received open-label aripiprazole, 15 or 30 mg per day, for six to 18 weeks. Patients achieving stabilization (YMRS score ≤ 10, MADRS score ≤ 13 for six consecutive weeks) entered the double-blind phase, at which point they were randomly assigned to treatment with aripiprazole or placebo for 26 weeks. The primary endpoint was time to relapse for any mood episode. Patients who remained in remission during the 26-week stabilization period continued in a double-blind fashion with aripiprazole or placebo for an additional 74 weeks and were monitored for relapse, efficacy, and tolerability. In total, 161 patients met the stabilization criteria and were randomly assigned to aripiprazole (N=78) or placebo (N=83). At 100 weeks, time to relapse was significantly longer with aripiprazole than placebo; the active drug was superior to placebo in delaying time to manic relapse. However, no significant differences were observed in time to depressive relapse. Adverse events for aripiprazole occurring in more than 5% of the subjects included tremor, akathisia, dry mouth, flu syndrome, and mild weight gain, among others. In conclusion, over a 100-week treatment period, aripiprazole monotherapy was effective for manic relapse prevention and maintained a good safety and tolerability profile [23]. In a post-hoc analysis of the 100-week maintenance study, patients with rapid cycling were identified and efficacy of aripiprazole monotherapy versus placebo was examined. In this group of cases, the active drug was statistically superior to no therapy in preventing affective recurrences in an otherwise recalcitrant manifestation of BD [42].

Clinical Implications of Acute and Long-term Aripiprazole Studies in Bipolar Mania
In view of the efficacy and safety data presented above, aripiprazole should be considered a first-line agent in the treatment of manic or mixed episodes in Bipolar I disorder patients. It can be preferentially administered in both new onset and recurrent mania, either as monotherapy or as an add-on to mood stabilizers, and may be used favorably in the acute and maintenance phases with the manic polarity of illness. Further, when patients experiencing a manic or mixed episode have less than optimal response to monotherapy with conventional mood stabilizers, aripiprazole is a valid choice as an adjunctive medication to induce remission.
Akin to schizophrenia, it is a switch option in bipolar patients who poorly put up with other antipsychotics due to side effects and should be preferred in the long term treatment of such cases to promote compliance. As demonstrated in acute and long-term RCTs, it has notably few adverse effects and is well tolerated as mono and adjunctive therapy, with lower discontinuation rates as compared to typical antipsychotics, for example, haloperidol. It should be used in preference to agents like olanzapine in patients with high body mass index, dyslipidemia, and glucose intolerance. When a metabolic syndrome is induced during the ongoing treatment of bipolar subjects with other SGAs, aripiprazole is a valid alternate medication. Correspondingly, it can be utilized as a switch option in patients who develop hyperprolactinemia, EPSE, QTc prolongation, drowsiness, and sedation with the use of either typical or second generation antipsychotics in the course of treatment of BD.

Third generation antipsychotics in the treatment of bipolar depression
Although the distinctive clinical feature of bipolar disorder is the abnormally elevated mood seen in manic exacerbations, it does not usually make up the most common affective state of the patients. The majority of bipolar patients spend much more time suffering from depressive manifestations, which may present as major depressive episodes, sub-syndromal symptoms, or mixed episodes [43]. Depressive states are often comorbid with other neuropsychiatric conditions like anxiety spectrum disorders and are the major source of morbidity and mortality in BD. Depressive symptoms frequently show resistance to the usual mood stabilizers and are incriminated in refractoriness and chronicity of the illness. Used either as monotherapy or adjunctively to mood stabilizers, third generation antipsychotics are emerging as a credible treatment option for bipolar depression. The latest positive published trial in this respect is with cariprazine, a novel antipsychotic that acts as a partial agonist at D2R and D3R and, like aripiprazole and brexpiprazole, is a multipurpose psychotherapeutic agent [44]. The next three sections evaluate the data regarding the efficacy of aripiprazole in the acute treatment and prophylaxis of bipolar depression. In the management of acute episodes in a major depressive disorder, aripiprazole is an established treatment as an add-on to standard antidepressants. However, this is not the case with acute bipolar depression as demonstrated in an RCT in which aripiprazole failed to separate from placebo on the primary efficacy measure of Hamilton Rating Scale for Depression when used with open adjunctive citalopram [46].

Post-hoc Analysis of Data from Aripiprazole Monotherapy Trials in Acute Bipolar I Depression
A pooled, post-hoc examination of data from the above-mentioned two randomized, controlled trials was undertaken and the outcome of aripiprazole monotherapy versus placebo was assessed based on the initial severity of depressive symptoms of the study subjects. This was achieved by categorizing cases as severely (Bech-6 total score > 15) or less severely depressed (Bech-6 total score < 15) using sub-sets of Bech-Rafaelsen scale. Efficacy was measured by mean variations in MADRS total and MADRS-6 subscale scores from the initiation of the trials to the endpoint at Week 8 using a mixed model, repeated measures analysis. In this manner, a sum of 133 patients (n = 62 on the active drug) was found to be severely depressed and 612 patients (n = 309 on aripiprazole) as less severely depressed. At Week 8, the mean MADRS total score reduction for severely depressed patients receiving aripiprazole compared with placebo was -19.4 vs. -15.4 (p = 0.14), whereas MADRS-6 subscale score reduction for patients receiving aripiprazole compared with placebo was -13.8 vs. -10.3 (p = 0.07). Adverse event profiles were similar between the two severity groups. The sum of the analysis was that improvement in essential depressive symptoms occurred with flexibly dosed aripiprazole monotherapy in subjects with more severe major depressive episodes than those with less severe manifestations in Bipolar I disorder [47].

Prevention of Depressive Relapse
Compared to placebo, aripiprazole monotherapy was shown in a maintenance study to delay time to manic relapse but not for depressive relapse after 26 and 100 weeks of treatment [23]. The inability of aripiprazole to reduce the time to depressive relapse in this study could be due to the enrollment of patients with index manic/mixed episodes, a manic polarity of illness, and consequently, lower occurrence of depressive relapses. Another long-term trial comparing aripiprazole and lithium in a head-to-head manner showed that both drugs were equally efficacious in preventing affective recurrences of manic and mixed type but the former agent did not obviate depressive relapses [41]. A 52-week trial comparing aripiprazole or placebo adjunctive to conventional mood stabilizers showed that the active drug, plus lithium or divalproex, was more effective in manic than depressive relapse prevention [22]. Although data does not support the efficacy of aripiprazole in precluding depressive relapses, there is a need for more and better-designed studies in this regard. One strategy may be to enroll bipolar patients with index depressive episodes in long-term aripiprazole trials, either as monotherapy or in conjunction with mood stabilizers. Further, when proposing protocols for novel psychotherapeutic agents in bipolar depression, exclusive reliance on efficacy measures like MADRS may not portray the whole picture. There is also an argument for including other parameters that assess general functioning, reduction in comorbidities, and decline in overall symptomatic burden [48]. It must not be forgotten that BD is linked to numerous comorbidities, chief among which are substance use disorders and anxiety spectrum conditions. Aripiprazole is a multifunction drug, and in addition to targeting core affective symptoms, it has important implications for the treatment of associated neuropsychiatric comorbidities in bipolar spectrum disorders.

Aripiprazole in the Adjunctive Treatment of Major Depressive Disorder (MDD)
MDD is a major psychiatric ailment and shares phenotypic, pathophysiologic, and prognostic characteristics with bipolar disorder. It is a recurrent condition and is often refractory to treatment with the usual antidepressant medications, resulting in continued morbidity in spite of optimal therapy with the latter agents. In this event, there is an enduring need for psychotherapeutic drugs, which are truly efficacious in MDD and can stall the vicious cycle of deterioration in the biopsychosocial domains. RCTs of aripiprazole have been conducted in this disorder, mainly as an adjunct to first-line antidepressants and salutary affects statistically demonstrated with standardized measures [49]. This is of significance, as MDD is a recalcitrant condition with neuroprogressive features, and aripiprazole, being the prototypical third generation antipsychotic, has opened fresh avenues in the overall treatment of this disorder.

New directions and emerging therapies for bipolar and related disorders
Partial agonism, functional selectivity, and serotonin-dopamine activity modulation are the new pharmacodynamic principles in the treatment of major psychiatric disorders, including bipolar spectrum disorders. In the case of aripiprazole, evidence from controlled trials supports its usefulness in acute manic and mixed episodes, rapid cycling, psychotic mania, and prevention of manic recurrences in Bipolar I disorder. It is an FDA approved therapy for schizophrenia and adjunctive treatment of MDD, which expounds the fact that aripiprazole is a versatile psychotherapeutic agent. As a further advancement in drug development, two new related compounds, brexpiprazole and cariprazine, have won FDA endorsement, while a number of other molecules are in different stages of experimentation. These are the latest "third generation antipsychotics" which are, in essence, multipurpose medications and have the promise of alleviating hitherto recalcitrant manifestations like cognitive and negative deficits associated with neuroprogressive psychiatric disorders [50]. As the deficit symptoms are responsible for the true burden of principal psychiatric diseases, the recent paradigm shift in pharmacotherapy is opening fresh avenues in the treatment of these conditions. It is beyond the scope of this manuscript to go into the details of published RCTs and ongoing studies of brexpiprazole and cariprazine, but novel antipsychotics hold the potential of improving the overall prognosis of patients with major psychiatric ailments. Table 4 gives FDA approved indications of aripiprazole, brexpiprazole, and cariprazine at the time of the writing of this manuscript. Figure 4 illustrates the therapeutic prospects of this group of medications.

FIGURE 4: Targeting neuropsychiatric symptoms in major mental disorders
Principal psychiatric disorders share the common feature of neuroprogression, which implies that there is increasing biopsychosocial impairment as the illness advances. Novel agents like aripiprazole, brexpiprazole, and cariprazine have the potential to treat various disease manifestations and be of value in affective, psychotic, cognitive, and negative symptoms.

Conclusions
Bipolar disorder is a highly disabling condition with a large number of patients remaining symptomatic either because they are refractory to the traditional mood-stabilizing medications or cannot tolerate these due to adverse effects. There is a pressing need for new and better drugs, which are efficacious in treating as well as preventing mood episodes in these patients. Aripiprazole is the first among the unique group of novel antipsychotics that is well studied in all phases of BD and controlled trials have been very helpful in delineating its place in the treatment of this chronic, life-long disorder. It is particularly efficacious in managing patients with the manic polarity of illness and is safe and well tolerated by the majority of treated subjects. Although controlled trials have not proven its worth in acute or recurrent bipolar depression, it may have a place in treating bipolar spectrum disorder patients with substance use and other comorbidities. Currently, it is highly recommended for the management of acute and recurrent mania in Bipolar I disorder. The same appears to be true for mixed episodes, rapid cycling, and psychotic mania. Considering its value in the treatment of anxiety spectrum and addictive disorders, it can be efficacious in bipolar subjects with these concomitant conditions. It is also the preferred agent in patients with metabolic abnormalities and those who are