European Review for Medical and Pharmacological Sciences 2012; 16: 1346-1354 Aripiprazole, and : a review

M. BRUNETTI1,2, L. DI TIZIO2, S. DEZI2, G. POZZI3, P. GRANDINETTI3,4, G. MARTINOTTI1,2

1Institute of Advanced Biomedical Technologies, University of Chieti, Italy 2 Department of Neuroscience and Imaging, School of Medicine, University of Chieti, Italy 3Institute of and Psychology, Department of Neuroscience, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy 4Department of Psychiatry and , Ludwig Maximilians University, Munich, Germany

Abstract. – Aripiprazole is an atypical an- manic and mixed episodes associated with bipo- tipsychotic used for schizophrenia, manic and lar I disorder and as adjunctive therapy for major mixed episodes associated with bipolar I disor- depressive disorder1. der and as adjunctive therapy for major depres- Aripiprazole is an atypical antipsychotic. It is a sive disorder. It functions as a partial agonist at D2 and 5-HT1A receptors, and as an quinolinone derivative that has a receptor binding antagonist at the 5-HT2A receptor. profile with a different mechanism of action com- The most recent results obtained from scien- pared to the other atypical antipsychotic drugs2. tific research showed that dopaminergic mech- The novel pharmacodynamics of aripiprazole anisms are involved in motivation, reward, and shows an important interaction with a great num- of substance abuse. The use of ber of G protein-coupled receptors3. Aripiprazole aripiprazole and partial dopamine agonists exhibits high affinity for dopamine D2 and D3, could represent a novel strategy for normaliz- ing dopamine neurotransmission. Many studies 5-HT1A (5-hydroxytryptamine 1A) and 5-HT2A in the last few years have highlighted aripipra- (5-hydroxytryptamine 2A) receptors, moderate zole as a potential candidate for the treatment affinity for the 5-HT reuptake site, and moderate of different types of . affinity for dopamine D4, 5-HT2C, 5HT7, α1- This review aims to describe recent scientific adrenergic and histamine H1 receptors. Aripipra- research using aripiprazole in different sub- zole functions as a partial agonist at dopamine stance abuse disorders (i.e., , co- D2 and 5-HT1A receptors, and as an antagonist caine, and use). Further- 3 more, the efficacy of aripiprazole compared to at the 5-HT2A receptor . It also presents an anti- other pharmacological therapies will be de- inflammatory effect via the inhibition of mi- scribed. croglial activation4, with a promising effect on Given the low number of studies, the fre- the cytokine production as showed by the newer quent absence of placebo or active compara- antidepressants5. Aripiprazole was shown to be tors, and the low statistical power of the stud- efficacious in different psychiatric disorders6-8 ies, a clear conclusion about the use of arip- 9,10 iprazole in alcohol/substance dependence can- with a favorable adverse event profile . not be drawn. Therefore, we suggest the need In the domain of substance use disorders, a for further studies, preferably randomized and novel strategy for normalizing dopamine neuro- placebo-controlled. transmission could be represented by the use of aripiprazole and partial dopamine agonists which Key Words: may help to reverse dopamine depletion, ob- Aripiprazole, Substance abuse, Dopamine agonist. served during withdrawal states, due to their flex- ible activity11. Considering the efficacy in de- creasing alcohol consumption, craving for alco- hol and psychiatric symptom intensity of other Introduction atypical antipsychotics acting on the dopaminer- gic/serotonergic systems, such as olanzapine12 The Food and Drug Administration (FDA) ap- and quetiapine13, aripiprazole should be given proved the use of Aripiprazole (ARI) for schizo- greater consideration for the treatment of sub- phrenia, for the management and maintenance of stance abuse12,14.

1346 Corresponding Author: Paolo Grandinetti, MD; e-mail: [email protected] Aripiprazole, alcohol and substance abuse: a review

Alcoholism aim of reversing dopamine depletion typically observed during ethanol abstinence11. Non-pharmacological treatments such as psy- The first two studies that investigated the effi- chotherapy, cognitive-behavioral therapy, group cacy of aripiprazole in were therapy, or residential treatment programs have performed by Martinotti et al in 2007 and by An- not yet obtained effective results with the alcohol ton in 2008. In the first study the Authors ob- use disorders15. In United States and Europe, on- served the efficacy of aripiprazole in decreasing ly a few medications are approved for the treat- alcohol use in substance abusers, lessening crav- ment of alcohol dependence, but these medica- ing and attenuating severity of psychopathologi- tions were only moderately successful16. Recent- cal symptoms. Thirteen detoxified alcohol-depen- ly, due to the better understanding of the neurobi- dent subjects were treated with flexible doses of ological substrates of alcohol dependence, new aripiprazole for 16 weeks; six patients maintained pharmacological treatments appeared17-20, and an alcohol free condition for the entire study peri- one of the main objectives of the scientific com- od but all the subjects experienced a reduction of munity is the integration of new pharmacothera- craving in both OCDS and VAS and a decrease of pies with non-pharmacological treatment ap- the SCL-90 General Severity Index (GSI)28. proaches15. Anton et al29 in a randomized, multicenter, Disulfiram, Naltrexone and Acamprosate21 are double-blind, placebo-controlled study, showed the three medications currently approved for the the efficacy and safety of aripiprazole, compared treatment of alcohol dependence in US, whereas to placebo. The study showed that, aripiprazole- in some EU countries there are other options, as treated subjects reported a more positive re- for Gamma hydroxybutyrate in Italy and Austria. sponse than placebo-treated subjects both in sub- Disulfiram, an aldehyde dehydrogenase in- jective effects and in craving. hibitor, blocks the oxidation of ingested alcohol Voronin et al30 tested the effects of aripiprazole at the acetaldehyde stage and prevents its metab- on alcohol consumption in thirty alcoholics. Pa- olism to acetate. For this reason, even small tients were divided into two groups; 15 were amounts of alcohol in a disulfiram treated pa- treated with aripiprazole (15 mg) and 15 were tient, cause tachycardia, hypotension, diaphore- treated with placebo for eight days. The utility of sis, flushing, dyspnea, nausea and vomiting as a aripiprazole was observed during the first six consequence of acetaldehyde accumulation22. days of treatment and, on day 8, during a free Naltrexone is an receptor antagonist. It choice limited access alcohol consumption para- reduces heavy drinking by diminishing the re- digm following an initial drink of alcohol in a warding neurobiological effects of alcohol23. It bar-lab setting. This study showed that aripipra- acts, in the ventral tegmental area and the nucle- zole was well tolerated and reduced the desire to us accumbens, on dopamine reward pathways drink again after the first drink, which was used and reduces both dopamine release24 and endoge- as bait, and broke the link between priming drink nous release25 in response to alcohol. induced stimulation and further drinking, espe- In 2004 the Food and Drug Administration ap- cially in more impulsive patients. With this study proved the use of acamprosate, or N-acetyl ho- Voronin et al30 suggested that aripiprazole would motaurine, a N-methyl-D-aspartate receptor improve impulse control (self control for alcohol) modulator which is, together with psychosocial by enhancing the function of frontal cortex in pa- support, a good treatment in detoxified alcohol- tients with alcohol dependence. dependent patients during maintenance therapy26. Recently different researchers have tried to de- According to a recent review by Edwards, termine if a combination of different drugs had a Kenna et al, serotonin-specific reuptake in- greater efficacy than either single drug taken hibitors (i.e., sertraline), prazosin, topiramate, ba- alone in reducing alcohol use in alcohol depen- clofen and ondansetron, and aripiprazole could dent patients. In 2009 Kenna et al19 investigated represent new neuropharmacological treatment the safety and tolerability of the aripiprazole-top- for alcohol dependence27. iramate combination in alcohol drinkers. All par- ticipants were treated with 300 mg of topiramate Aripiprazole and Alcohol use Disorders and 30 mg of aripiprazole for 36 days resulting For many years researchers have tried novel in a reduction of alcohol use by participants. strategies to normalize dopamine neurotransmis- Moreover there was no evidence of adverse ef- sion, using partial dopamine agonists, with the fects from the combination of these two drugs

1347 M. Brunetti, L. Di Tizio, S. Dezi, G. Pozzi, P. Grandinetti, G. Martinotti and, therefore, the Authors concluded that the impulsive behavior33. In patients who developed combination could be administered safely with a a dependence it was shown that these areas were modest amount of alcohol. affected by a dysregulation, given the putative Other researchers have conducted specific stud- activity of aripiprazole on these areas, this drug ies in dual-diagnosis patients assuming a possible could be beneficial for the treatment of alco- correlation between alcoholism and psychiatric dis- holism. Furthermore, supporting this hypothesis, orders. A randomized, double-blind, comparison it was demonstrated that in animal models of al- trial with naltrexone investigated the efficacy of coholism aripiprazole produced an overall de- aripiprazole on alcohol-drinking indices, craving crease in drinking behavior34. and improvement of psychiatric symptoms31. In this In 2012, a study on mice investigated the ef- study craving and withdrawal rating scales were ap- fect of aripiprazole on ethanol-induced psycho- plied. Psychiatric symptoms were evaluated logical and physiological dependence and anxi- through the Symptom Check List 90-Revised. The ety-like behavior. This study observed the effect number of subjects remaining alcohol free for the of aripiprazole on the development and expres- entire study period (16 weeks) and the number of sion of ethanol-induced place preference with the relapsing subjects was not significantly different in result that aripiprazole-treatment yielded a posi- the two groups, but the survival function showed tive outcome, suggesting that aripiprazole can be that patients treated with aripiprazole remained ab- effective for reversing ethanol-induced place stinent from any amount of alcohol for a longer preference and anxiety-like behavior. time with respect to those treated with naltrexone. Also, patients treated with naltrexone showed a bet- ter outcome, in terms of craving scores, compared to those treated with aripiprazole. In recent years, neuroimaging studies aimed at Cocaine remains the second most commonly investigating aripiprazole effects on brain activa- used illicit drug in Europe. Although prevalence tion were also conducted. Myrick et al32 using levels and trends differ considerably between fMRI, observed brain activation in alcoholics. countries, almost everywhere the use of this drug Non-treatment-seeking alcoholics were randomly remains limited, excepted for a small number of assigned aripiprazole (15 mg) or placebo for 14 western European countries where high levels of days. Then each patient underwent functional cocaine use are observed. There is also a substan- magnetic resonance imaging, they were given a tial diversity among cocaine users, divided into sip of alcohol before measuring changes in re- occasional users, who usually snort cocaine pow- gional brain activity while they were viewing al- der and most avid consumers, who inject cocaine coholic and nonalcoholic-beverage randomized or use crack cocaine35. pictures. During the scanner sessions subjects The available drugs for the treatment of cocaine rated their urge to drink. The Authors showed an abuse or dependence are relatively ineffective36. The increased activation in the right ventral striatum different hypotheses that researchers have recently for placebo-treated subjects, while there was a formulated relating to the various mechanisms im- lower activation in the same areas in the aripipra- plicated in cocaine suggest several promis- zole treated patients. Moreover, during the 14- ing pharmacological approaches37. The most day medication period, a reduction of heavy promising medications for dependency seem to be drinking was observed in aripiprazole-treated agents such as GABA agents (topiramate, tiagabine, subjects. The study provides both novel and valu- baclofen and vigabatrin) and agonist replacement able information regarding the effect of aripipra- agents (, disulfiram, ). zole on cue-induced brain activation and volun- Furthermore, the results from trials of first- and sec- tary drinking during treatment. The important ond-generation neuroleptics were not promising. findings provided from this study clarified the Nevertheless, in order to clarify remaining uncer- role of the ventral striatum for brain dopamine tainties, larger, randomized, placebo-controlled stud- balance: the was clearly a ies are needed36,38. critical point implicated in the dopaminergic sys- It is also important to note that other drugs al- tem and in the maintenance of heavy drinking in ready studied for other indications, like Disulfi- alcoholics. ram39 and Vigabatrin40 were shown to have an ef- Moreover it was demonstrated that the frontal- ficacy and an anti-cocaine vaccine has also subcortical circuits subserve reward/craving and shown promise41.

1348 Aripiprazole, alcohol and substance abuse: a review

Finally, optimal therapeutic platforms that ond most commonly used illicit substance after combined pharmacotherapies with behavioral in a few other countries always in Eu- therapies37 and psychosocial treatments were use- rope35. ful in supporting the pharmacotherapy of cocaine Although cognitive behavior interventions, abuse36. cognitive behavior therapy, family education, support, and counseling may give some advan- Aripiprazole and Cocaine Use Disorders tages, there are no randomized controlled trials Several studies were conducted with the aim indicating that psychosocial treatment was really of testing the safety, tolerability, and subject-rat- effective in decreasing intravenous amphetamine ed effects of acute intranasal cocaine administra- use47.. tion during aripiprazole maintenance. In 2007 in Various neuronal mechanisms implicated in a randomized, placebo-controlled study, Stoops dependence suggest several et al42 observed eight cocaine dependent subjects pharmacological approaches. As reported in a fo- maintained with 10 mg oral aripiprazole and cused review of 2010 pharmacological approach- placebo. Their results indicated that aripiprazole es using high number of drugs to methampheta- did not have considerable effects, although it did mine dependence was not effective, but modify temperature-increase and subject-rated modafinil, and naltrexone, in double- effects of cocaine with dose. In 2008, Lile et al43 blind placebo-controlled trials showed some performed a similar study to evaluate the proto- promising effects. In addition studies employing typical -like effects of cocaine com- agonist replacement medications, with d-amphet- pared with placebo, finding that aripiprazole in- amine and with methylphenidate, have shown to creased these effects. be effective, but a pharmacotherapy options to A few years later, in 2011, the same Researchers44 manage abstinence have not been identified37. tested discriminative stimulus, subject-rated and This observation was shared by Brackins et al48, cardiovascular effects of cocaine alone and in com- who conducted a literature review on pharmaco- bination with aripiprazole, demonstrating that logical treatments for methamphetamine use and acutely administered aripiprazole attenuated dis- addiction. The Authors pointed out that Aripipra- criminative stimulus. This efficacy of treatment in zole trials appeared more frequently than the oth- acute was in agreement with previous studies that er medications within the reviewed literature. tested aripiprazole in combination with acutely ad- This work indicates that, at the moment, no sin- ministered d-amphetamine. It seems clear, there- gle medication demonstrated a consistent effica- fore, that, according to this study the ability of cy in . aripiprazole to modify stimulant effects of drugs One reason of these results could be method- depended on the duration of treatment. These re- ological, given that the typical stimulant abuser is sults agreed with Meini et al45 who recently con- often a polysubtsance dependent and for this rea- ducted a 12-week clinical trial on cocaine depen- son is a more difficult subject; this factor was not dence patients, comparing aripiprazole and ropini- always included in clinical trials49. role in order to determine their safety, tolerability Furthermore, this review revealed that all the and effects. The Authors demonstrated that arip- considered studies included several methodologi- iprazole was more efficacious than ropinirole in re- cal limitations that need to be overcome in future ducing cocaine use while cocaine craving de- studies if effective pharmacotherapy options to creased with aripiprazole treatment as well as enhance abstinence are to be found48. ropinirole treatment. Nevertheless, a different point of view was provided in 2011 by Haney et al46 that Aripiprazole and Disorders Induced by in their study, showed that aripiprazole seemed to Amphetamine and Methamphetamine increase cocaine self administration in humans to During the last ten years, several studies veri- compensate for a blunted subjective cocaine effect. fied the effectiveness of aripiprazole in ampheta- mine dependence treatment. A study was conducted in 2007 with the pur- Amphetamine and Methamphetamine pose of comparing the effectiveness of aripipra- zole, methylphenidate, and placebo in the treat- Amphetamines and ecstasy are usually the ment of amphetamine dependence. Urinalysis most commonly used illicit drugs in many Euro- was used as an objective measure of primary pean countries, though they have become the sec- outcome. The results of this study provided an

1349 M. Brunetti, L. Di Tizio, S. Dezi, G. Pozzi, P. Grandinetti, G. Martinotti unfavorable result for the use of aripiprazole in Nicotine the treatment of amphetamine dependence. When compared to placebo group, in fact, ARI addiction, the second-leading cause treatment was found to correspond to a greater of death worldwide, is correlated with approxi- number of amphetamine-positive urine mately 5 million deaths each year. Currently, samples47. With the same goal in 2008, in a dou- there are about 1.3 billion smokers; most (84%) ble-blind in-patient clinical pharmacology study, live in developing countries54. “With the present Newton et al50 investigated the tolerability and smoking trends, tobacco will kill 10 million peo- effectiveness of aripiprazole, with the aim of as- ple each year by 2020”55. sessing the interactions between intravenous Due to the complexity of the type of depen- methamphetamine and oral aripiprazole. The dence, nicotine replacement therapies have been Authors concluded that aripiprazole treatment developed. These therapies gradually release had negligible effects on the pharmacokinetics nicotine into the body to facilitate withdrawal of methamphetamine since “higher ratings on while allowing the smoker to break the behav- Addiction Research Center Inventory subscales ioral habits associated with the cigarette itself. reflecting euphoria, significant reductions in rat- Nicotine gum is available in 2-mg and 4-mg ings of ‘bad effects’ and reductions on the ARCI pieces and is sold without a prescription56. Nico- subscale for sedation effects following Meth tine patches are a system designed to deliver dosing” were found. nicotine transdermally over a 16- or 24-hour pe- More recently, using a different perspective in riod maintaining nicotine levels for a longer peri- comparison to the previous studies, Sevak et al51 od than any other system57. studied discriminative-stimulus, subject-rated, Another agent (non-nicotine based) that can be and physiological effects of methamphetamine in used to facilitate is bupropion. humans pretreated with aripiprazole. The study In clinical trials bupropion was well tolerated, the assessed the effects of a range of doses of only adverse events more common with bupropi- methamphetamine (0, 2.5, 5, 10, and 15 mg), on than placebo were and dry mouth alone and in combination with 0 and 20 mg of and it prevented weight gain even if it should be aripiprazole. The results thus obtained differed noted that the drug was effective only in a long from the conclusions of previous studies. In their term therapy58. patients the discriminative-stimulus and cardio- Varenicline, a partial α4β2 and full α7 nico- vascular effects together with the subject-rated tinic receptor agonist, was approved by the FDA drug effects, were significantly attenuated by ad- in 2006 for the treatment of . ministration of aripiprazole. A different study by Its activity seems related to the inhibition of nico- Narendran et al52 using positron emission tomog- tine self-administration, through the action on raphy (PET), measured the amphetamine-in- dopamine balance in the nucleus accumbens56. In duced dopamine (DA) release. These Authors three studies comparing varenicline with bupro- evaluated the action of specific ligands in the hu- prion and placebo, “varenicline 1 mg resulted in man cerebellum by detecting a change in 52-week continuous abstinence rates of 21% to [¹¹C]FLB 457 V(T) following aripiprazole which 23% (95% confidence intervals ranging from ranged from –33 to –42% in the regions of inter- 17% to 28%), whereas buproprion and placebo est (ROIs). The result of this study suggested an produced rates of 14% to 16% (95% confidence important interaction between aripiprazole and interval 11%-20%) and 4% to 10% (95% confi- specific binding sites in the cerebellum that could dence interval 1%-13%)”, respectively60. be used in future drug treatments. Finally, in 2011, a complex study by Steed et Aripiprazole and Nicotine Consumption al53 analyzed the ability of the serotonin reuptake The central dopaminergic system has a central inhibitor fluvoxamine to alter methamphetamine- role in the mechanism of reinforcement of the induced hyperactivity. In this work aripiprazole nicotine effects and consequently in the urge to was used just for comparative purposes, together smoke. In literature before 2010 two cases of with haloperidol, terguride, and clozapine. The smokers who responded positively to aripipra- results of this study emphasized that 1mg/kg of zole were reported. aripiprazole was the minimal effective dose nec- Sriram Ramaswamy et al61 reported the first in essary to attenuate methamphetamine-induced 2006. A case of “a man with a major depressive locomotor activity. disorder that during his hospital stay, initiated

1350 Aripiprazole, alcohol and substance abuse: a review aripiprazole therapy and that subsequently dis- The most recent results obtained from scien- charged on aripiprazole and other medication no- tific research showed that dopaminergic mecha- ticed a lack of “high” from the cigarettes as well nisms are involved in motivation, reward, and as fewer cravings for nicotine use, his Modified reinforcement of substance abuse. It is becom- Fagerstrom Tolerance Questionnaire score de- ing increasingly clear that in addicted subjects creased to zero and the patient attributed these a decreased dopamine function produces a con- results to aripiprazole. He continued to be nico- gruent decreasing in the sensitivity to non- tine abstinent for the next 2 weeks until he ran drug-related stimuli and a reduction in the in- out of aripiprazole, while off aripiprazole thera- hibitory frontal function. These last two aspects py, he relapsed and went back to smoking. Ap- contribute to compulsive drug intake and com- proximately a week later, he resumed aripipra- promise inhibitory control65. To this respect zole therapy and was simultaneously able to quit Voronin et al30 suggested that aripiprazole smoking again”. would improve impulse control (self control for Another study was reported by Arbaizar62 in alcohol and substance) by enhancing the func- 2008, that described a decrease in tobacco con- tion of frontal cortex. sumption after treatment with topiramate and Regarding the serotonin system, the 5-HT1A aripiprazole. The mentioned case concerns “a 34- partial agonist effect of aripiprazole may modu- year-old man who compulsively smoked 80 to late prefrontal cortex to improve impulse control 100 cigarettes each day and that after receiving through the projections from the raphe nucleus to treatment with topiramate and aripiprazole, dra- the ventral tegmental area and nucleus accum- matically reduced his tobacco consumption”. bens (Walsh and Cunningham, 1997)66. Taken to- Starting from these cases and other clinical evi- gether, these findings suggest that dopamine re- dence, in the last two years some clinical studies lease induced by aripiprazole might be associated were conducted on heavy smokers and smoking with increased activation of anterior cingulate schizophrenic patients. A recent study in 2010 in- which may control craving for alcohol and sub- vestigated the urge to smoke in two particular mo- stances. ments of the day, at awakening and immediately Many studies in the last few years highlighted following meals, in heavy smokers treated for 2 aripiprazole as a potential treatment candidate for weeks with 10-mg aripiprazole, demonstrating that different types of dependence, with good evi- in treated patients an important decrease of waking dence in alcohol, cocaine, amphetamine and to- and postprandial urges to smoke were observed63. bacco use disorders, as described in this review. In another study64, this time in patients with a Moreover, in our opinion, aripiprazole could also positive history of smoking but also having a previ- represent a possible alternative in subjects with ous diagnosis of schizophrenia, the effects of poly-substance-abuse, a condition characterized haloperidol and three atypical antipsychotics by higher level of psychiatric, and in those sub- (risperidone, olanzapine, and aripiprazole) on the stance/alcohol abusers with high level of impul- reduction of the urge to smoke were evaluated. sivity and novelty seeking67,68. However, given These patients were interviewed about the need to the low number of studies, the frequent absence smoke and cigarette craving at baseline and follow- of placebo or active comparators, and the low ing eight weeks of treatment. Patients included in statistical power of these studies, a clear conclu- the haloperidol group reported that the urge to sion cannot be drawn. Therefore we suggest that smoke increased, whereas patients belonging to further studies are required, mainly randomized atypical antipsychotics groups and specifically pa- placebo-controlled, to determine the real efficacy tients treated with aripiprazole, reported a reduc- of this molecule in the treatment of dependence. tion both in nicotine dependence and cigarette craving. References

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