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Clinical News
Peter F. Buckley, MD
Phase 1 Results of New Putative
Antipsychotic Use in Anorexia
Antipsychotic RP5063 Reported
Nervosa: Mouse Model Provides
Results were presented at the recent New Clinical Drug New Evidence
Evaluation Unit (NCDEU) Conference on a Phase 1 study Klenotich and colleagues recently provided an elegant of a putative antipsychotic RP5063 in 55 subjects. The agent series of studies in rodents to address and explain the po- was found to have antipsychotic effects on positive symp- tential benefit of antipsychotics—in this instance olanzap- toms of psychosis and appeared to be wel tolerated. A Phase ine—in the treatment of anorexia nervosa. Although this 2 study is now under development. RP5063 is an agent with is very clearly an off-label use of these drugs, antipsychot- selective partial agonist effects on dopamine D2 and sero- ics have long been used as an adjunct for recalcitrant an- tonin 5HT1A, as wel as dopamine antagonism at D3 and orexia nervosa. It has been considered that their potential D4 dopamine receptors. More information available at www.
benefit is not just to “put on weight” in these patients. This study created an animal model of anorexia—Activity-Based Intramuscular Aripiprazole: New Data
Anorexia (ABA)—and optimized its expression through We have previously highlighted in CS the development
food access. The authors report that olanzapine given over of an intramuscular (IM) formulation of aripiprazole. A time reduces ABA in mice, an effect that was not seen with double-blind, placebo-controlled study of 710 patients with fluoxetine. The authors did not find that this effect could be schizophrenia that was conducted over four phases with a explained through sedation or hyperphagia. They concluded total study duration of one year found that intramuscular that neurochemical changes related either to dopamine and aripiprazole was effective in reducing the time to (“impend- reward circuits, or related to alterations in hypothalamic ing”) relapse (10% in IM group versus 39.6% in placebo pituitary adrenal (HPA) axis activity during chronic thera- group). Symptoms also improved on intramuscular aripip- py. Of course, the study could not address whether mood- razole compared with placebo, and there was also a statisti- related changes with antipsychotic therapy might also help cal y greater improvement in social functioning in patients in controlling symptoms of anorexia nervosa.
receiving aripiprazole. Intramuscular aripiprazole was gen- Klenotich SJ, Seiglie MP, McMurray MS, Roitman JD, Le Grange D, Dugad eral y wel received, with weight gain observed in 6.4% of P, et al. Olanzapine, but not fluoxetine, treatment increases survival in activ- ity-based anorexia in mice. Neuropsychopharmacology 2012;37(7):1620- patients versus 5.2% of patients receiving placebo. Injection site pain was recorded during the maintenance-treatment phase among 3% of patients receiving intramuscular aripip- Study of Zonisamide for
razole and among 3.7% of patients receiving placebo (“dur- Antipsychotic-Related Weight Gain
Susan McElroy and colleagues have recently provided us with a thoughtful study that evaluates the potential of Results from a Clinical Phase 3 Study of Once-Monthly Aripiprazole In- tramuscular (IM) Depot Formulation for the Maintenance Treatment of zonisamide—an anti-epileptic drug that has also been used Schizophrenia Presented at APA Annual Meeting. May 7, 2012. Available (importantly, in an off-label, non-FDA approved approach) in treating mood disorders—to ameliorate antipsychotic- Staccato Loxapine under
related weight gain. This group had previously studied topi- Continued Review by the FDA
ramate in a similar manner. In this study, they assessed In previous issues of CS we have highlighted the deliv-
zonisamide versus placebo add-on to olanzapine over ery system as wel as key findings from clinical trials of the 16 weeks of therapy in 40 patients. There was overal less putative antipsychotic staccato loxapine—an inhalant form weight gain on zonisamide, although patients receiving this of loxapine. The U.S. Food and Drug Administration (FDA) drug also experienced more cognitive impairment (25% of has recently requested some clarification from the pharma- patients versus 0% in the placebo group). This is, of course, a ceutical company, although no clinical y substantive issues “hot” area of research in the psychopharmacology of schizo- were brought forward by the FDA at this time. Staccato loxapine has been shown in clinical trials to be effective for McElroy SL, Winstanley E, Mori N, Martens B, McCoy J, Moeller D, et al. the treatment of acute agitation in psychotic patients. More A randomized, placebo-controlled study of zonisamide to prevent olanzap- information available at www.alexza.com.
ine-associated weight gain. J Clin Psychopharmacol 2012;32(2):165-172. Clinical Schizophrenia & Related Psychoses July 2012 • 000
Clinical News
Can Antipsychotic-Related Weight
German Multicenter Study of Relapse
Gain be Genotyped?
in Schizophrenia
A very recent multicenter, international study by Mal- Schennach and colleagues recently examined the course hotra and colleagues conducted a pharmacogenetic analy- of illness in the first year following hospital discharge in 200 sis of susceptibility to antipsychotic-related weight gain in a patients with schizophrenia. At the end of this year, 25% combined sample of 344 subjects who were treated with var- of patients were on treatment with first-generation antipsy- ious second-generation antipsychotic medications (SGAs). chotic (FGA) medications while 65% of patients received The duration of treatment was between 6 and 12 weeks second-generation antipsychotic medications. The study (maximum) for al patients. The study showed an associa- also il ustrates how people traverse in their illness over time tion—through a genome-wide association study (GWAS) between relapse, remission, and recovery. It also highlights examining polymorphisms—of the melanocortin 4 recep- that patients who relapsed over time were more likely to be tor (MC4R) gene and weight gain liability. This was also ex- receiving FGA medications, to have a poor attitude toward tended to metabolic measures such as insulin and lipid. The medication compliance, and to be unemployed. rs489693 genotype pattern of expression was also replicated Schennach R, Obermeier M, Meyer S, Jager M, Schmauss M, Laux G, et in al of the cohorts in this study. It is also important, how- al. Predictors of relapse in the year after hospital discharge among patients ever, to appreciate that while the MC4R gene was implicated with schizophrenia. Psychiatr Serv 2012;63(1):87-90.
in this study, the specific single-nucleotide polymorphisms (SNPs) of rs489693 was less prominent than other SNPs Is Childhood Adversity a Risk Factor
associated with weight gain in the general population.
for Schizophrenia?
Malhotra AK, Correl CU, Chowdhury NI, Muller DJ, Gregersen PK, Lee We have previously highlighted literature that addresses AT, et al. Association between common variants near the melanocortin 4 this fundamental issue: can childhood trauma (and, if so, receptor gene and severe antipsychotic drug-induced weight gain. Arch what types of trauma) bring on schizophrenia? Bental and Gen Psychiatry 2012 May 7. [Epub ahead of print] colleagues have careful y culled the literature from sev- Polypharmacy in Schizophrenia:
eral complimentary vantage points to clarify this potential Relationships to Suicide and Non-
relationship. They too found an over representation of later development of schizophrenia in children who have had Suicidal Deaths
some sort of trauma before 16 years of age. They also report The practice of polypharmacy is common—if not ubiq- that the effect of different sources of trauma may impact the uitous—in the treatment of people with schizophrenia. The symptom profile—with childhood physical and sexual abuse extent to which such practices improve outcomes—reduced more associated with auditory hal ucinations while paranoia relapse, improved symptoms—is debated amidst a highly is associated with childhood neglect/institutionalization. variable literature that points to largely idiosyncratic effects. The association between childhood rape and hal ucinations The adverse effect profile and long-term risks of such aug- appeared quite robust (observed ratio 8.9). The study also mentation strategies is of course “the flip side of the coin.” A reports “dose response relationships” for each trauma. These recent study by Tiihonen and colleagues cites no difference findings are both interesting and provocative, although there in mortality between patients receiving two antipsychot- are several limitations to this study including diagnosis, ics and those treated with antipsychotic monotherapy. The symptom capture, and reliance/over interpretation of ques- same result was observed for patients who also received con- comitant antidepressant medications. On the contrary, how- ever, patients receiving benzodiazepines had higher mortal- Bental RP, Wickham S, Shevlin M, Varese F. Do specific early-life adver- sities lead to specific symptoms of psychosis? A study from the 2007 The ity rates, both from suicide and from non-suicidal causes of Adult Psychiatric Morbidity Survey. Schizophr Bul 2012 April 10. [Epub death. This is an important study and further informs the ongoing concern regarding premature death among people Readers wishing to know more about the details of individu- Tiihonen J, Suokas J, Suvisaari JM, Haukka J, Korhonen P. Polypharmacy al studies cited in Clinical News should consult directly the
with antipsychotics, antidepressants, or benzodiazepines and mortality in pharmaceutical company who sponsored the study and/or schizophrenia. Arch Gen Psychiatry 2012;69(5):476-483. 000 • Clinical Schizophrenia & Related Psychoses July 2012

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