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Aripiprazole Partial Agonism at 5-HT2C: A Comparison of Weight Gain Associated With Aripiprazole Adjunctive to Antidepressants With High Versus Low Serotonergic Activities

Aripiprazole Partial Agonism at 5-HT2C: A Comparison of Weight Gain Associated With Aripiprazole Adjunctive to Antidepressants With High Versus Low Serotonergic Activities

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ABSTRACT

Objective: 5-HT2C receptor antagonists are thought to contribute toward increased appetite and obesity. Aripiprazole acts as a partial agonist at the 5-HT2C receptor; hence, it is thought to cause little or no significant weight gain when used alone. We theorize that, in the presence of antidepressants with high serotonergic activity, aripiprazole acts as an antagonist at the 5-HT2C receptor, thus increasing the potential for weight gain. Conversely, in environments with low serotonergic activity, aripiprazole acts as an agonist at the 5-HT2C receptor, therefore having less potential for weight gain.

Method: A retrospective electronic medical record chart review of the Veterans Integrated Service Network 22 Veterans Affairs database was performed comparing patients’ weight and body mass index (BMI) while taking aripiprazole alone (n = 1,177), versus aripiprazole plus a high-serotonergic antidepressant (citalopram, fluoxetine, paroxetine, sertraline, or venlafaxine) (n = 145), versus aripiprazole plus a low-serotonergic antidepressant (bupropion) (n = 77) for a minimum continuous duration of 6 months of aripiprazole monotherapy or combination treatment. The study was conducted from January 2010 through June 2011.

Results: In our patient population, only the aripiprazole plus high-serotonergic antidepressants group had a statistically significant increase in weight (P = .0027) and BMI (P = .0016).

Conclusions: Our data suggest that, in the presence of antidepressants with high serotonergic activity, aripiprazole may act as an antagonist at the 5-HT2C receptor, resulting in weight gain. Conversely, when aripiprazole is used in the presence of antidepressants with low serotonergic activity, it may act as an agonist and result in little or no weight gain. This varying effect at the 5-HT2C receptor may explain why aripiprazole has not been associated with significant weight gain in previous studies focusing on schizophrenia and bipolar disorder.

Prim Care Companion CNS Disord 2012;14(5):doi:10.4088/PCC.12m01386

Submitted: March 29, 2012; accepted June 1, 2012.

Published online: October 18, 2012.

Corresponding author: Jennifer A. Rosen, PharmD, BCPP, VA Long Beach Healthcare System (600/119), Long Beach, CA 90822 (jennifer.rosen@va.gov).

Most antipsychotic medications are associated with an increased risk of weight gain. A proposed mechanism is the antagonism at the 5-HT2C receptor, which has been associated with an increase in food intake.1 In contrast, agonism at the 5-HT2C receptor, as produced by fenfluramine and m-chlorophenylpiperazine, may lead to suppression of appetite.2,3 Tecott and colleagues4 developed a strain of mice lacking the gene for the 5-HT2C receptor. These mice demonstrated increased obesity. In a meta-analysis, De Luca et al,5 looking primarily at the 759C/T promoter polymorphism (rs3813929) of the X-chromosome-linked HTR2C gene, provided data suggesting a 5-HT2C-receptor association with weight changes; however, they noted heterogeneity among the studies and suggested the need for larger studies. Furthermore, a study by Kirk et al6 showed a significant increase in weight in rats after 5 days of daily doses of olanzapine and the 5-HT2C antagonist SB 243213 but not the histamine-1 (H1) antagonist. Stark et al,7 using the 5-HT1B/2C agonist m-chlorophenylpiperazine and subsequently a 5-HT1B and 5-HT2C antagonist in non-anesthetized male rats, showed decreased fast-induced refeeding only with 5-HT2C.

In support of the previous data, there are important molecules interacting with the brain nervous system that regulate feeding and energy balance by influencing the signaling pathways of these areas. Only a few of these mediators have been described. In a recent publication, Wang et al8 showed that Abelson helper integration site 1 (Ahi1) protein directly influences 5-HT2C. Fasting increases Ahi1, which leads to decreased expression of 5-HT2C.8 Subsequently, knockdown of Ahi1 leads to increased expression of 5-HT2C, which results in decreased food intake and body weight.

Opgen-Rhein et al,9 looking at 128 patients with schizophrenia, demonstrated an association between the X-chromosomal HTR2C gene and antipsychotic-induced weight gain. They proposed that the underlying mechanism is related to a decrease in HTR2C gene expression that leads to a decrease in 5-HT-modulated activation of hypothalamic proopiomelanocortin neurons and inverse 5-HT2C agonism in the presence of dopamine-2 (D2) receptor antagonism. However, De Luca et al, looking at 3 functional polymorphisms (Cys23Ser, −759C/T, and (GT)12-18/(CT) 4-5) of the HTR2C gene in 139 patients with schizophrenia, reported no significant haplotype conferring risk for antipsychotic-induced weight gain.5 In another study, Martin et al10 randomized 39 patients to lorcaserin (a 5-HT2C agonist) and 28 patients to placebo and demonstrated that weight loss is a result of decrease in energy intake, not as an increase in energy expenditure. Wang and Chehab11 looked at the interaction between leptin and the 5-HT2C in proopiomelanocortin neurons in regulating body weight. In a population of transgenic mice with overexpressing leptin (LepTg), without 5-HT2C receptors, they demonstrated that, on a lean diet, the phenotype of LepTg mice was unaffected by the absence of 5-HT2C receptors, whereas on a high-fat diet, LepTg/5-HT2C-receptors-knockout mice showed an exacerbation of diet-induced obesity. Thus, on a carbohydrate-rich diet (or “chow diet”), the LepTg works independently of 5-HT2C, while on a high-fat diet, the 5-HT2C is needed for attenuation of obesity.

clinical points
  • There is still much to be learned about the mechanism(s) behind antipsychotic-induced weight gain.
  • One theory behind aripiprazole’s varying effects on weight gain is that, in the presence of high serotonergic activity, aripiprazole acts as an antagonist at the 5-HT2C receptor, thus increasing the potential for weight gain. Conversely, when in an environment of low serotonergic activity, aripiprazole acts as an agonist at the 5-HT2C receptor, thereby having less effect on weight.
  • Further research into the 5-HT2C receptor and other receptor subtypes and their relation to appetite and obesity is still needed.

Preliminary evidence suggests that aripiprazole is a partial agonist at 5-HT2C.12 In the presence of antidepressants with high serotonergic activity, aripiprazole may act as an antagonist at the 5-HT2C receptor, thus increasing the potential for weight gain. In environments with low serotonergic activity, aripiprazole may act as an agonist at the 5-HT2C receptor, thus having less effect on the potential for weight gain.12 This varying effect at the 5-HT2C receptor may explain why aripiprazole has not been associated with significant weight gain in previous studies focusing on schizophrenia and bipolar disorder. Therefore, we hypothesize that adjunctive use of aripiprazole along with antidepressants with low serotonergic activities may result in less weight gain compared to aripiprazole when used in the presence of antidepressants with high serotonergic activity.

METHOD

A retrospective electronic medical record chart review of the Veterans Integrated Service Network (VISN) 22 Veterans Affairs (VA) database from January 1, 2003, until December 31, 2009, was performed after institutional review board approval (VISN 22 covers VA patients from all of Southern California and parts of Nevada). The chart review compared patients’ weight and body mass index (BMI) while taking aripiprazole alone (n = 1,177), versus aripiprazole plus a high-serotonergic antidepressant (citalopram, fluoxetine, paroxetine, sertraline, or venlafaxine; n = 145), versus aripiprazole plus a low-serotonergic antidepressant (bupropion; n = 77). Patients had to be on continuous treatment for a minimum of 6 months, with continuous treatment defined as having no breaks in treatment greater than 90 days (Figure 1). Data were extracted electronically through an automated process. Extraction was repeated to ensure quality control of the data. The study was conducted from January 2010 through June 2011.

Figure 1

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The baseline BMI was based on the last weight taken in the 180-day period prior to the start of aripiprazole monotherapy or combination drug therapy (T0). The follow-up BMI was based on the first weight taken between 180 to 360 days after start of therapy.

We excluded patients with a lapse of drug therapy of 90 days or more, patients who were lost to follow-up, patients without sufficient data, and patients who had more than a 100-lb change in weight over the prior 6 months, assuming these were errors on data entry in the medical chart.

Three groups were identified:

Group 1: Aripiprazole monotherapy of at least 180 days’ duration.

Group 2: Citalopram (50.3%), fluoxetine (18.6%), paroxetine (8.3%), sertraline (16.6%), or venlafaxine (6.2%) added to existing aripiprazole with at least 180 days of combination therapy.

Group 3: Bupropion added to existing aripiprazole with at least 180 days of combination therapy.

Data gathered were analyzed using SPSS, version 14 software (IBM, Armonk, New York) for standard deviation (SD), paired sample test and t test 2-tailed analysis, and analysis of variance.

RESULTS

All 3 groups were relatively similar at baseline, with the exception of a difference in age, BMI, and sex (Table 1). In the patients taking aripiprazole without an antidepressant (n = 1,177), patients gained a mean of 0.79 lb (SD = 17.31 lb) and had an increase in BMI of 0.11 kg/m2 (SD = 2.55 kg/m2), although neither change was statistically significant.

Table 1

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In patients taking aripiprazole with a high-serotonergic antidepressant (n = 145), there was a statistically significant mean increase in weight of 3.91 lb (SD = 15.48 lb) (P = .0027), as well as a statistically significant mean increase in BMI of 0.60 kg/m2 (SD = 2.24 kg/m2) (P = .0016).

In the third group, patients taking a combination of aripiprazole and a low-serotonergic antidepressant (n = 77), patients lost a mean of 0.53 lb (SD = 15.3 lb) and had a mean decrease in BMI of 0.09 kg/m2 (SD = 2.31 kg/m2), although neither change was statistically significant (Table 2).

Table 2

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DISCUSSION

Antipsychotic medications, both first- and second-generation, have the potential side effect of weight gain, with second-generation agents carrying a greater risk.13-17 Allison et al18 performed a meta-analysis comparing the weight gain of first- and second-generation antipsychotic medication. In this analysis, clozapine was found to be associated with the greatest weight gain, followed by olanzapine, risperidone, and ziprasidone, respectively. Parsons et al,19 in a more recent comprehensive database analysis, found a median weight increase over 1 year of +0.49 lb/mo for haloperidol, −0.18 lb/mo for ziprasidone, +1.50 lb/mo for olanzapine, and +0.55 lb/mo for risperidone, compared to placebo, which demonstrated a weight loss of 0.32 lb/mo.

Based on the results of our study, it appears that aripiprazole may indeed exhibit varying effects at the 5-HT2C receptor, possibly acting as an antagonist in the presence of antidepressants with high serotonergic activity. Several studies demonstrate that aripiprazole is a partial agonist at 5-HT2C.12 Aripiprazole may be an agonist in environments with low 5-HT2C stimulation and an antagonist in conditions of high 5-HT2C stimulation.12 In the presence of antidepressants with high serotonergic activity, aripiprazole may act as an antagonist at the 5-HT2C receptor, thus increasing the potential for weight gain. In environments with low serotonergic activity, aripiprazole may act as an agonist at the 5-HT2C receptor, thus having less potential for weight gain. This varying effect at the 5-HT2C receptor may explain why aripiprazole has not been associated with significant weight gain in previous studies focusing on schizophrenia and bipolar disorder.

Antagonism at the histamine-1 (H1) receptor has also been associated with weight gain.20-24 Wirshing et al25 found an exponential relationship between the medications’ H1 receptor affinities (dose-dependent) and maximum weight gain. Both olanzapine and clozapine have very strong binding affinity to both 5-HT2C and H1 receptors compared to other antipsychotic medications, which may explain increases in appetite and thus weight gain, while peripheral M3 muscarinic receptor antagonism also contributes to obesity (which might explain the dose-dependent weight gain with these medications and not with other second-generation antipsychotic medications.26,27

Multiple studies28-33 have established aripiprazole, a partial agonist at several G-protein-coupled receptors (D2 and 5-HT1A) and functional antagonist at several serotonin receptors, including 5-HT2A, 5-HT2B, and 5-HT6, as an effective treatment for symptoms of schizophrenia and bipolar mania, with a low potential for weight gain. In long-term studies in schizophrenia and bipolar disorder,34,35 aripiprazole treatment has not been associated with a mean increase in body weight from baseline. In some cases, small decreases in mean body weight have been observed.36,37 However, in a study38 with aripiprazole adjunctive to standard antidepressant therapy, particularly escitalopram, fluoxetine, paroxetine, sertraline, or venlafaxine, for patients with DSM-IV major depressive disorder, the weight gain associated with aripiprazole (3.74 lb) is significantly higher than with placebo (0.88 lb). Our results support this observation that patients on a combination of a high-serotonergic antidepressant with aripiprazole showed a statistically significant increase in weight of 3.91 lb (P = .0027), as well as a statistically significant increase in BMI of 0.60 kg/m2 (P = .0016).

CONCLUSION

In our study, patients taking a combination of a high-serotonergic antidepressant with aripiprazole showed a statistically significant increase in weight of 3.91 lb, as well as statistically significant increase in BMI of 0.60 over 6 months. However, those patients taking aripiprazole without an antidepressant had no significant changes in either weight or BMI over 6 months. Those patients taking aripiprazole with a low-serotonergic antidepressant also showed no significant changes in weight or BMI over the 6-month period.

We theorize that aripiprazole’s partial agonism at the 5-HT2C receptor explains the weight gain found in studies in which aripiprazole is used as adjunctive treatment with antidepressants.

This study supports the limited data regarding weight gain liability in patients treated with a combination of high-serotonergic antidepressants and aripiprazole. Further studies are needed to understand the mechanisms involved and consequently to minimize side effects, such as weight gain and its implications.

Drug names: aripiprazole (Abilify), bupropion (Wellbutrin, Aplenzin, and others), citalopram (Celexa and others), clozapine (Clozaril, FazaClo, and others), escitalopram (Lexapro and others), fluoxetine (Prozac and others), haloperidol (Haldol and others), olanzapine (Zyprexa), paroxetine (Paxil, Pexeva, and others), risperidone (Risperdal and others), sertraline (Zoloft and others), venlafaxine (Effexor and others), ziprasidone (Geodon).

Author affiliations: Departments of Mental Health (Dr Nguyen) and Pharmacy (Dr Rosen), Veterans Affairs Long Beach Healthcare System, Long Beach, California; Voluntary Faculty, Department of Psychiatry and Human Behavior, University of California Irvine Health Sciences (Dr Nguyen); University of the Pacific School of Pharmacy, Stockton, California, and University of Southern California School of Pharmacy, Los Angeles (Dr Rosen); and Department of Psychiatry, University of Missouri-Kansas City School of Medicine and Kaiser Permanente, Riverside, California (Dr Bota).

Potential conflicts of interest: Dr Nguyen is on the speakers bureau for and has received honoraria from Bristol-Myers Squibb. Drs Rosen and Bota have no conflicts of interest to disclose.

Funding/support: None reported.

Previous presentation: Data from this study were presented in part at the 50th Annual Meeting of the New Clinical Drug Evaluation Unit; June 14-17, 2010; Boca Raton, Florida.

Acknowledgments: The authors acknowledge Michael Juzba, PharmD, MS, Department of Pharmacy, Veterans Affairs Long Beach Healthcare System, Long Beach, California, for assistance with data extraction and analysis. Dr Juzba has no conflicts of interest to disclose.

REFERENCES

1. Aulakh CS, Hill JL, Yoney HT, et al. Evidence for involvement of 5-HT1C and 5-HT2 receptors in the food intake suppressant effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Psychopharmacology (Berl). 1992;109(4):444-448. PubMed doi:10.1007/BF02247721

2. Garattini S, Mennini T, Samanin R. Reduction of food intake by manipulation of central serotonin: current experimental results. Br J Psychiatry suppl. 1989;(8):41-51. PubMed

3. Walsh AE, Smith KA, Oldman AD, et al. m-Chlorophenylpiperazine decreases food intake in a test meal. Psychopharmacology (Berl). 1994;116(1):120-122. PubMed doi:10.1007/BF02244883

4. Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature. 1995;374(6522):542-546. PubMed doi:10.1038/374542a0

5. De Luca V, Mueller DJ, de Bartolomeis A, et al. Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol. 2007;10(5):697-704. PubMed doi:10.1017/S1461145707007547

6. Kirk SL, Glazebrook J, Grayson B, et al. Olanzapine-induced weight gain in the rat: role of 5-HT2C and histamine H1 receptors. Psychopharmacology (Berl). 2009;207(1):119-125. PubMed doi:10.1007/s00213-009-1639-8

7. Stark JA, McKie S, Davies KE, et al. 5-HT(2C) antagonism blocks blood oxygen level-dependent pharmacological-challenge magnetic resonance imaging signal in rat brain areas related to feeding. Eur J Neurosci. 2008;27(2):457-465. PubMed doi:10.1111/j.1460-9568.2007.06002.x

8. Wang H, Huang Z, Huang L, et al. Hypothalamic Ahi1 mediates feeding behavior through interaction with 5-HT2C receptor. J Biol Chem. 2012;287(3):2237-2246. PubMed doi:10.1074/jbc.M111.277871

9. Opgen-Rhein C, Brandl EJ, Müller DJ, et al. Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics. 2010;11(6):773-780. PubMed doi:10.2217/pgs.10.50

10. Martin CK, Redman LM, Zhang J, et al. Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure. J Clin Endocrinol Metab. 2011;96(3):837-845. PubMed doi:10.1210/jc.2010-1848

11. Wang B, Chehab FF. Deletion of the serotonin 2C receptor from transgenic mice overexpressing leptin does not affect their lipodystrophy but exacerbates their diet-induced obesity. Biochem Biophys Res Commun. 2006;351(2):418-423. PubMed doi:10.1016/j.bbrc.2006.10.033

12. Zhang JY, Kowal DM, Nawoschik SP, et al. Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms. Biochem Pharmacol. 2006;71(4):521-529. PubMed doi:10.1016/j.bcp.2005.11.007

13. Meltzer HY. Beyond serotonin. J Clin Psychiatry. May 1991;52(suppl):58-62. PubMed

14. Meltzer HY. The mechanism of action of novel antipsychotic drugs. Schizophr Bull. 1991;17(2):263-287. PubMed

15. Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther. 1989;251(1):238-246. PubMed

16. Jann MW. Clozapine. Pharmacotherapy. 1991;11(3):179-195. PubMed

17. Moore NA, Rees G, Sanger G, et al. Effects of olanzapine and other antipsychotic agents on responding maintained by a conflict schedule. Behav Pharmacol. 1994;5(2):196-202. PubMed doi:10.1097/00008877-199404000-00011

18. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696. PubMed

19. Parsons B, Allison DB, Loebel A, et al. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res. 2009;110(1-3):103-110. PubMed doi:10.1016/j.schres.2008.09.025

20. Wilson JD, Hillas JL. Astemizole: a new long-acting antihistamine in the treatment of seasonal allergic rhinitis. Clin Allergy. 1983;13(2):131-140. PubMed doi:10.1111/j.1365-2222.1983.tb02580.x

21. Knight A. Astemizole—a new, non-sedating antihistamine for hayfever. J Otolaryngol. 1985;14(2):85-88. PubMed

22. Howarth PH, Emanuel MB, Holgate ST. Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels. Br J Clin Pharmacol. 1984;18(1):1-8. PubMed

23. Rockwell WJ, Ellinwood EH Jr, Trader DW. Psychotropic drugs promoting weight gain: health risks and treatment implications. South Med J. 1983;76(11):1407-1412. PubMed doi:10.1097/00007611-198311000-00021

24. Bernstein JG. Psychotropic drug induced weight gain: mechanisms and management. Clin Neuropharmacol. 1988;11(suppl 1):S194-S206. PubMed

25. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry. 1999;60(6):358-363. PubMed doi:10.4088/JCP.v60n0602

26. Reynolds GP, Kirk SL. Metabolic side effects of antipsychotic drug treatment—pharmacological mechanisms. Pharmacol Ther. 2010;125(1):169-179. PubMed doi:10.1016/j.pharmthera.2009.10.010

27. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? a literature review. J Clin Psychiatry. 2009;70(7):1041-1050. PubMed doi:10.4088/JCP.08r04392

28. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400-1411. PubMed doi:10.1038/sj.npp.1300203

29. Davies MA, Sheffler DJ, Roth BL. Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology. CNS Drug Rev. 2004;10(4):317-336. PubMed doi:10.1111/j.1527-3458.2004.tb00030.x

30. Newcomer JW. Second-Generation (atypical) Antipsychotics and Metabolic Effects: A Comprehensive Literature Review. CNS Drugs. 2005;19(suppl 1):1-93. PubMed doi:10.2165/00023210-200519001-00001

31. Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302(1):381-389. PubMed doi:10.1124/jpet.102.033175

32. Keck PE Jr, McElroy SL. Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic. Expert Opin Investig Drugs. 2003;12(4):655-662. PubMed doi:10.1517/eoid.12.4.655.23750

33. Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol. 2002;441(3):137-140. PubMed doi:10.1016/S0014-2999(02)01532-7

34. Kasper S, Lerman MN, McQuade RD, et al. Efficacy and safety of aripiprazole vs haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol. 2003;6(4):325-337. PubMed doi:10.1017/S1461145703003651

35. Keck PE Jr, Calabrese JR, McQuade RD, et al; Aripiprazole Study Group. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67(4):626-637. PubMed doi:10.4088/JCP.v67n0414

36. McQuade RD, Stock E, Marcus R, et al. A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomized, double-blind study. J Clin Psychiatry. 2004;65(suppl 18):47-56. PubMed

37. Pigott TA, Carson WH, Saha AR, et al; Aripiprazole Study Group. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry. 2003;64(9):1048-1056. PubMed doi:10.4088/JCP.v64n0910

38. Trivedi MH, Thase ME, Fava M, et al. Adjunctive aripiprazole in major depressive disorder: analysis of efficacy and safety in patients with anxious and atypical features. J Clin Psychiatry. 2008;69(12):1928-1936. PubMed doi:10.4088/JCP.v69n1211

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