Aripiprazole Treatment in the Adolescent Patients
with Inhalants Use Disorders and Conduct Disorder:
A Retrospective Case Analysis

Assoc. Prof., Zonguldak Karaelmas Üniversity, Medical Faculty, Departmant of Child and Adolescent Psychiatry, Zonguldak MD, Zonguldak Karaelmas Üniversity, Medical Faculty, Departmant of Child and Adolescent Psychiatry, Zonguldak Corresponding Author: Dr. Ayten Erdogan, Zonguldak Karaelmas Üniversitesi, Çocuk ve Ergen Psikiyatrisi, Zonguldak, Turkey
E-mail address: [email protected]
Tel: +903722610169
Fax: +902122514511
Aripiprazole Treatment in the Adolescent Patients with Inhalants Use Disorders and Con-
duct Disorder: A Retrospective Case Analysis
Pharmacologically, aripiprazole is a partial agonist at D2 and 5-HT1A receptors and an antagonist
at 5-HT2A receptors with the different effect on dopaminerjic system from other antipsychotics.
Partial agonists are effective for stimulants, opiate, cocaine and nicotine dependence and dopami-
ne D2 receptors have been implicated in the abuse related effects of substances. In addition, it has
shown that aripiprazole reduced substance use in schizophrenic, bipolar or schizoaffective disor-
der patients comorbid with substance use disorders, suggesting that aripiprazole would be useful
in patients with substance use disorders and co-existing psychiatric conditions. Open-label eviden-
ce is also available for use of aripiprazole in disruptive behavior disorders in children and adoles-
cent. Therefore, aripiprazole might be an effective strategy for adolescent patients with inhalants
use disorders and conduct disorder. In the reported cases, aripiprazole treatment successfully cont-
rolled on psychiatric symptoms of adolescent patients and also reduced the frequency of substan-
ce use in these patients.
Keywords: aripiprazole, adolescents, inhalants, conduct disorder
Uçucu Madde Kullan›m Bozuklu¤u ve Davran›m Bozuklu¤u Olan Ergenlerin Tedavisinde
Aripiprazol Kullan›m›: Bir Retrospektif Vak’a Analizi
Aripiprazol dopaminerjik sistem üzerine di¤er antipsikotik ilaçlardan farkl› bir etkiye sahip olup;
dopamin D2 ve serotonin 5HT2A reseptörlerine k›smî agonist, serotonin 5HT1A reseptörüne anta-
gonist etki eden yeni nesil bir antipsikotikler ajand›r. D2 ve 5HT2A reseptörlerinin ba¤›ml›l›k etiyo-
lojisinde rol oynad›¤› bilinmektedir. Stimülanlar, opiat, kokain ve nikotin kötüye kullan›m› ve ba-
¤›ml›l›¤› tedavisinde D2 parsiyel agonistlerin kullan›lmas›n›n etkili oldu¤u bildirilmektedir. Ek ola-
rak kokain kullan›m› olan bipolar bozukluk ve flizofreni hastalar›nda aripiprazol tedavisi sonras›
madde kullan›m›n›n s›kl›¤›n› azaltt›¤›n›n tespit edilmifltir. Bu nedenle aripiprazol tedavisinin mad-
de kullan›m bozuklu¤una efllik eden psikiyatrik bozukluklar›n tedavisinde kullan›labilece¤i düflü-
nülmektedir. Aripiprazol D2 ve serotonin 5HT2A reseptörlerine etkisi nedeniyle çocuk ve ergenler-
de y›k›c› davran›fl bozukluklar›n›n tedavisinde ümit verici bir seçenek olabilece¤i bildirilmektedir.
Bu yaz›da uçucu madde kullan›m bozuklu¤u ve davran›m bozuklu¤u tan›s› alan ve tedavide aripip-
razol kullanan hastalar›n incelenmesi ve tart›fl›lmas› amaçlanm›flt›r. Bu bildirimde uçucu madde kul-
lan›m bozuklu¤u olan ve tedavide aripiprazol kullanan vak’alar incelenmifltir. Tan›mlanan 7 vak’a-
da aripiprazol tedavisi sonras› psikiyatrik belirtiler üzerinde kontrol sa¤lanmas›n›n yan›nda madde
kullan›m›n›n s›kl›¤›n›n azald›¤› tespit edilmifltir.
Anahtar Kelimeler: aripiprazol, ergenler, uçucu maddeler, davran›m bozuklu¤u
New/Yeni Symposium Journal • www.yenisymposium.net | Cilt 48 | Say› 3
O’Brien 2000). Open label study of aripiprazole in DSM-IV-TR (APA 2000) provides two broad catego- schizophrenic and bipolar outpatients with comorbid ries of substance-related disorders. The first category is cocaine dependence and alcohol-dependent patients substance use disorders (substance abuse and substan- indicates that aripiprazole can reduce alcohol and co- ce dependence) which are characterized by maladapti- caine use as well as cocaine and alcohol craving in this ve patterns of substance use. In addition to posing se- grup of patients (Beresford et al. 2005, Brown et al.
rious medical risks to the user, substance abuse and 2005). We hypothesized that aripiprazole as a partial dependence has also been associated with a number of agonist might be a treatment choice of inhalant use di- psychosocial problems and additional risk behaviors.
sorder as well. We herewith report a group of patients (Howard and Jenson 1999, Mcgarvey et al. 1996). Most with inhalant abuse and conduct disorder who were of these substance users have cormorbid conduct di- successfully treated with aripiprazole for more than 6 sorder, attention-deficit/hyperactivity disorder months. To our knowledge, this is the first case series (ADHD), major depressive disorder, dysthymic disor- using aripiprazole in the treatment of inhalant abuse der, alcohol dependence and psychosis (Evren et al.
2006; Grant et al. 2004; Mackesy-Amiti and Fendrich,1999; Hernandez-Avila et al. 1998). Accurate assess- ment of comorbid mental disorders is essential in the This study was conducted at the Department of development of effective interventions for adolescents Child and Adolescent Psychiatry, Faculty of Medicine, with substance disorders (Shane et al. 2003).
Karaelmas University in Zonguldak, Turkey. The files Inhalant drugs are widely available and frequently of adolescents with substance use disorders and con- misused, especially by adolescents (Hansen and Rose duct disorder who had been admitted to Child and 1995). Inhalants are appealing to adolescents for a va- Adoelscent Psychiatry outpatient and inpatient unit riety of reasons. They are relatively inexpensive; legal; between September 2007 and September 2009 were and readily available in homes, offices, supermarkets, screened retrospectively. All the patients’ prescription hardware stores, and drug stores (Kurtzman et al.
charts and medical records were reviewed in order to 2001, Wu and Howard 2007). Inhalant drugs are most identify those who were diagnosed as substance use widely misused substances in Turkey (Kaya and Öz- disorder and conduct disorder and treated with api- can 1999, Yazman 1995). The most commonly abused riprazole. The files of the patients are scanned and so- inhalants among Turkey adolescents are toluene, glue, ciodemographical data, psychiatric disaeses, alcohol shoe polish, lighter fluid, and gasoline (Ögel et al.
and frequency of inhalants use were noted. Apiripra- 2001). Recurrent inhalant use is associated with seri- zole dosage, treatment duration and side effects was ous health problems including cerebellar ataxia, Par- kinsonism, encephalopathy, trigeminal neuropathy, The criteria for inclusion were patients under 18 hepatorenal syndrome, hepatotoxicity, and “sudden years of age receiving apiriprazole for conduct disor- sniffing death” (Meadows and Verghese 1996, Maruf der comorbid with inhalants use disorders. In order to et al. 1998). Numerous studies indicate that inhalant enroll in the study, all patients were required to have abuse can be a predictor of polysubstance abuse, par- a minimum of six months of follow-up. The criteria ticularly the use of intravenous drugs (Boruette and for exclusion were lacking follow-up information, prescriptions for more than one antipsychotic on the Aripiprazole is a D2 partial agonist, resulting in a same date, using more than one substance. Subjects high occupancy of D2 but also 5-HT2 receptors in hu- dependent on any additional drug and alcohol were mans (Burris et al. 2002). Open-label evidence is also available for use of aripiprazole in bipolar disorders, Diagnostic and Statistical Manual of Mental Disor- psychotic disorders and disruptive behavior disor- ders, Fourth Edition, criteria used for substance use ders including conduct disorder and ADHD (Findling disorders and for the other psychiatric diagnoses. In et al. 2009). Because the stimulation of the mesolimbic routine clinical assesments The Turgay DSM-IV Dis- dopamine system plays a major part in substances’s ruptive Behaviour Disorders Scale was used for the addictive effect, the dopamine receptor blocking ef- disruptive behavior disorder diagnoses and sympto- fects of antipsychotic drugs have made them of inte- matology. A Clinical Global Impression-Improvement rest as potential pharmacotherapy for abuse and de- Score (CGI) was extracted from the report of the 1., 3., pendence treatment (Wee et al. 2007, Childress and 6. months treatment visit, compared to the initial eva- New/Yeni Symposium Journal • www.yenisymposium.net | Cilt 48 | Say› 3
luation. Data collected from medical, laboratory and calation had been postponed in these patients. Two of pharmacy records was noted and entered into a SSPS the patients (28.59%) on aripiprazole were taking me- database. Relations between two or more variables tilfenidat for treatment of ADHD, and three of the pa- were described by (chi)2 test, t-test.
tients (42.8%) were taking selektif serotonine reuptakeinhibitor (SSRI) for depressif disorders.
After approximately six months of follow-up, all Fourteen adolescents were reached at the end of fi- patients improved significantly more as manifested by le scanning. Two patients excluded from the study for their endpoint CGI. Fig. 2 demonstrated the mean CGI lacking follow-up information and one patient exclu- scores in cases. The mean CGI scores improved from ded for using more than one antipsychotic on the sa- 4.03±0.91 (1. month) to 3.61±1.13 (2. months) and me date. Two of them were not taken into this study 3.14±1.05 (6. months). The change of CGI-S scores bet- since they had been using more than one substance.
ween treatment months was statisticaly significant Another two subjects who did not come to follow up (p<0,05; p<0,01 respectively). Four of 7 patients visits were also excluded. Eligible cases consist of 7 (57.1%) were abstinent from inhalants in the treatment male patients between 12-17 years old (mean age of period of 3 month. After 6 months o)f treatment, there 15.53±11.27 years). Males comprised 100% of the was a trend for a decrease in the number of use days sample. Three patients (42.8%) dropped out primary per month in other 3 patients (3.4±2. vs 1.7±1.4; p=0.01 school and others were educated through the high school level (47.2%), two of these patients having oneyear loss in the high school. Demographic and clinical DISCUSSION
characteristics of the sample are presented in Table 1.
The main findings of this cases study were that ari- All eligible patients (7 men) in the present study piprazole improved the patient's conduct disorder fulfilled current Diagnostic and Statistical Manual of symptoms severity and reduced the amount of inha- Mental Disorders, Fourth Edition; criteria for inha- lant use (reducing use per day and increasing days lants abuse disorder and conduct disorder. The type of abstinent) and during treatment and observation peri- the substance used was toulen in all 7 patients, none of od. Aripiprazole appeared to be safe and well tolera- the patients fulfilled DSM IV criteria for inhalants de- ted in the current study population. The side effects pendence disorder. Among four patients occasionaly that were reported here were similar to those reported having alcohol, 2 had experienced psychotic symp- in a clinical trial of aripiprazole (Anton et al. 2008). Si- toms associated with inhalants use, but those symp- milar to our findings an open-label study of aripipra- toms were transient, and none of our patient fulfilled zole treatment in children and adolescents with con- DSM IV criteria for schizophrenia. Three of the 7 pati- duct disorder reported improvements in CGI scores of ents (42.8%) needed hospitalizasyon during the treat- For most antipsychotics, the therapeutic window For these 7 patients, the mean dose of aripiprazole occurs between 60 and 80%of striatal occupancy.Hig- was 10.8±5.6 mg (5–20). During the treatment in these her levels of receptor occupancy by these drugs lead to 7 patients, 2 subjects had mild agitation (one at a do- extra-pyramidal side-effects, while aripiprazole has a sage of 5 and the other at a dosage of 15 mg per day), safer profile even though it occupies more than 90% of and one had akathisia (15 mg per day), whereas 2 ot- receptors (Burris et al. 2002). This partial agonistic ef- hers had daytime sleepiness (one at a daily dosage of fect of aripiprazole led to the hypothesis that this com- 5 and the other one with 10 mg). None of these side ef- pound may act as a dopamine stabilizer. Thus, this fects required a cessation of the treatment, but dose es- modulatory action of aripiprazole may explain why in Table 1: Demographic and clinical characteristics of the sample
Mean age 15.53±11.27 Age of onset of substance use 11.16±9.66 Duration of substance use New/Yeni Symposium Journal • www.yenisymposium.net Temmuz 2010 | Cilt 48 | Say› 3
Table 3. The mean Clinical Global Impression-Improvement Scores
First month
Third month
Sixth month
*p<0,05; **p<0,01Clinical Global Impression-Improvement (CGI) the present study aripiprazole reduced the inhalant (Kurtzman et al. 2001). Some of the antipsychotic mo- use of patients. Also as dopamine abnormalities, par- re commonly studied for this purpose are for example ticularly in the frontal lobe, might underlie impulsive haloperidol, olanzapine, quetiapine, clozapine and responses, a feature of conduct disorder, and also ad- risperidone (Hart 2005). Aripiprazole also might be ef- diction, the potential ability of aripiprazole to stabilize fective in special populations of substance use disor- dopamine, particularly in the frontal cortex, might un- der patients. For example, in schizophrenic patients, derlie its effectiveness in those patients with less self- aripiprazole decreased the number of cocaine-positive control (Findling 2008, Greenaway and Elbe 2009).
urines, and in another study in patients with bipolar There has been increasing interest in the use of me- or schizoaffective disorder, aripiprazole reduced coca- dications that affect the dopamine receptor in the treat- ine craving, suggesting that aripiprazole would be ment of addiction. Antipsychotics have been candida- useful in cocaine-dependent individuals with co-exis- tes for the treatment of addiction for their ability to ting psychiatric conditions (Beresford et al. 2005; block dopamine receptors and counterbalance the inc- Brown et al. 2005). Thus, the efficacy of aripiprazole to rease in dopaminergic activity related with drugs’ ef- manage inhalants abuse and dependence remains to fects (Smelson et al.1997). In animals, at lower doses, aripiprazole increases dopamine release in precortical One limit of this study is the absence of urinary areas, but at slightly higher doses, reduces dopamine sampling, estimation of inhalant use being made only release in the nucleus accumbens (Li et al. 2004). This is on declarative data. However, in these patients with a unique pharmacological profile for an antipsychotic heavy medical, psychiatric, and social consequences agent. Particularly, their action on serotoninergic sys- of inhalant abuse, clinicians noticed an improvement tem has been regarded with interest, given the involve- ment of serotonin neurotransmission in addictive be-haviour (Burris et al. 2002). This unique combination CONCLUSION
lends itself for potential use in addiction. Given the ef- In conclusion, we report the case series of aripipra- fects of addictive substances, including alcohol, on zole in treatment of inhalant abuse disorders comor- ventral striatum?nucleus accumbens dopamine release bid with conduct disorder. In the present cases, the pa- and frontal cortical dopamine effects, a drug like ari- tient's conduct disorder symptoms severity and frequ- piprazole could hold great promise as a potential agent ency of inhalant use were significantly reduced with to reverse or block these effects (Anton et al. 2008). In aripiprazole treatment. Taken together, our data sug- fact, there have been a few small open label studies gest that aripiprazole may find utility in the treatment which suggest that aripiprazole was efficacious in re- of inhalant use disorders in adolescent who has co- ducing cocaine (Beresford et al. 2005) use, attenuating morbid conduct disorder. This study should enhance the effects of amphetamine challenge (Lile et al. 2005) research on the partial agonist hypothesis to treat in- and reducing alcohol use (Warsi et al. 2005) in humans.
halants abuse and dependence. Further controlled stu- Furthermore inhalants use can lead to symptoms dies are required to confirm its efficacy in patients of mimicking psychosis with hallucinations, paranoia etc and the use of anti psychotics relieve these symptoms New/Yeni Symposium Journal • www.yenisymposium.net Temmuz 2010 | Cilt 48 | Say› 3
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