 |
 |
|
|
|
Drug abuse is highly prevalent in schizophrenia patients. An estimated 50% of subjects diagnosed with schizophrenia also present SUDs, compared with 12% of the general population (1). Cannabis, alcohol, and cocaine are the substances most commonly used by these patients (1,2). It is considered that substance abuse hastens the onset of schizophrenia, aggravates its symptoms, leads to poorer therapeutic compliance, and increases hospitalizations in this population (3,4). Despite high comorbidity and the impact of substance use on the outcome of schizophrenia, controlled studies assessing the effectiveness of pharmacologic treatment in this type of patient are rare (5). In 2 recent studies, risperidone decreased relapse for substances more than typical neuroleptics in subjects with schizophrenia and substance abuse (6–7). However, owing to compliance problems, many psychiatrists tend to prefer using depot neuroleptics to ensure better compliance and to reduce exacerbations and hospitalization in these patients (8,9). Bearing in mind the scarcity of controlled studies in this field, we opted to carry out the first controlled study comparing long-acting injectable risperidone and zuclopenthixol-depot in subjects with schizophrenia and SUDs. Risperidone is an atypical antipsychotic widely used in the treatment of schizophrenia patients (10). It has been shown that long-acting injectable risperidone improves schizophrenia symptoms in stabilized patients treated with typical or atypical antipsychotics when switched to it (11). Zuclopenthixol is a well-established thioxanthene antipsychotic. Zuclopenthixol’s controlled studies have shown that this antipsychotic is as effective as chlorpromazine (12) and risperidone (13) in the treatment of schizophrenia patients. It can be administered intramuscularly or orally. The objective of the present study was to compare the efficacy of the 2 drugs in improving substance abuse in subjects with dual diagnosis. At the same time, we aimed through this comparison to determine which antipsychotic drug would improve schizophrenia symptoms and produce better compliance with the psychotherapeutic program for managing substance abuse. MethodChronic schizophrenia patients with SUDs were enrolled for a randomized, controlled study carried out at 2 outpatient centres in Spain. The study was performed in accordance with the Helsinki Declaration (1964) (see www.cirp.org/library/ethics/helsinki/). Approval of the protocol by appropriate local ethics committees was also secured. We obtained a written informed consent in all cases. Patients To be eligible for inclusion, patients were between the ages of 18 and 65 years, with a diagnosis of schizophrenia and SUD for substances other than caffeine and nicotine, according to the Structured Clinical Interview for DSM-IV (14). Patients were excluded from the study if they had a clinically significant organic or neurologic disorder, serious psychotic disorder other than schizophrenia, clinically relevant abnormalities in laboratory tests at baseline, neutropenia or thrombocytopenia, or a clinically relevant abnormal ECG. Patients were selected during their stay in hospital. They had been admitted owing to a worsening of their psychotic symptomatology. Once stabilized, and before being discharged, they were asked if they would participate in the study. Of 183 patients interviewed, 115 agreed to participate. Design Patient selection took place while patients were in hospital. When informed consent was obtained, subjects were allocated alternately to receive long-acting injectable risperidone or zuclophentixol-depot. They remained in hospital for an additional 7 to 15 days, until being referred to their outpatient centre to continue pharmacologic treatment for 6 months. Before hospital discharge, patients were given a baseline interview. They had a weekly consultation with their psychiatrist, who was responsible for prescription and monitoring of the risperidone and zuclopenthixol and for the program to prevent substance use relapses. At each weekly visit, patients also took a urine test to check for alcohol, opiates, cocaine, and cannabis (InstaCheck Drug Screen Test, Applied Biotech/Forefront Inc, San Diego, CA). Every 2 months, subjects were interviewed by a monitor with no knowledge of their pharmacologic treatment, until the 6-month follow-up period was complete (total 24 weeks). Patients could ask to drop out of the study at any time. Failure to attend the interviews or to take the urine test during follow-up was not considered sufficient reason to exclude subjects from the study. Patients who had to be admitted to a psychiatric hospital during the follow-up period were given the opportunity of continuing the study if they wished. If the patient failed to attend the bi-monthly visit (for example, because he or she was hospitalized), the interview was postponed until it was possible for the patient to attend. Justification of the Design We chose an open design to avoid the typical complications that may arise in double-blind studies with substance abusing patients. The emergence of adverse reactions and (or) severe side effects may lead blind researchers to exclude the patient from the study when, in many cases, secondary reactions to substance use are involved. To avoid the possible bias resulting from assessment of the patient by the clinician (who was obviously aware of the treatment prescribed), we opted to include blind assessors. We used a long follow-up period in view of the fact that changes of habit related to substance use are difficult and take considerable time. Thus the conditions of the study are as close as possible to those of normal practice. Blind Researchers The outcome data were collected by researchers who were blinded to the drug taken by the patients. Every 2 months, they interviewed subjects and filled out the different efficacy and safety scales. Assessment Instruments Evaluation of SUDs and use of substances. Although patients were asked about substance use in each of the interviews, we included detection of substances in urine as measures of substance-use assessment in the weekly tests. Reactive strips were used for alcohol, cocaine, opiates, and cannabis (Instacheck, San Diego, CA). Severity of the complications of substance use was assessed by the Addiction Severity Index (15). Evaluation of Efficacy on Schizophrenia Symptoms. Efficacy was assessed with the PANSS (16) for schizophrenia and the Clinical Global Impression scale (17). Evaluation of Safety. Extrapyramidal symptoms were evaluated with the ESRS (18). The effects of other adverse events on the patients’ daily activities were evaluated by means of the UKU Side Effect Rating Scale (19). Psychotherapeutic Program Roberts and colleagues (20) developed the SAMM program, which comprises the following modules: basic training (8 sessions), skills training (9 sessions), and practical sessions. It is based on a cognitive-behavioural approach and is designed specifically for patients diagnosed with schizophrenia and substance abuse. All the subjects attended this type of psychotherapeutic session weekly until the completion of 24 sessions. Outcome Variables The main outcome variable was the number of positive urine tests during the follow-up period. Time elapsed before the first positive urine test was also evaluated. The secondary outcome variables were:
Statistical Analysis Measures of efficacy and safety were analyzed according to the intent-to-treat principle. Unpaired t tests were used to analyze differences between treatment groups. Dichotomous variables were evaluated with Pearson’s chi square test or 2-tailed Fisher’s exact test. Variations in each of the variables in a given treatment group were analyzed with 2-tailed paired t test. We used a last observation carried forward model for repeated-measures analysis and employed a significance level of 0.05 to characterize the results. We determined the number of patients with negative urine tests at the end of Month 6 with the Kaplan-Meier product-limit survival test. We used different regression models to explain the clinical response to substance use (two-thirds of the urine controls were negative), clinical response of the psychopathology (PANSS total < 20% of baseline), and compliance with the psychotherapeutic program (75% attendance at sessions) at the end of the follow-up period. ResultsThe demographic and baseline characteristics did not differ significantly between the 2 treatment groups (Table 1). Patients were treated with oral neuroleptic drugs prior to commencement of the trial (haloperidol 80% and chlorpromazine 20%).
During the follow-up period, 9 of 115 patients dropped out of the study, 6 from the zuclopenthixol-depot group and 3 from the long-acting risperidone group. Five of these were rehospitalized and spent 6 months as inpatients. The other 4 did not agree to attend the program for the management of substance abuse. Ten of 57 patients from the long-acting risperidone group and 11of 58 subjects from the zuclopenthixol-depot group needed to be admitted to a psychiatric hospital during this period owing to exacerbation of their psychopathological symptoms. At the end of the follow-up, the risperidone group was treated with 47.2 mg per 15 days of long-acting risperidone and 3.4 mg daily (range 2 mg to 6 mg) of oral risperidone. The zuclopenthixol group was also receiving 200 mg of zuclopenthixol-depot every 21 days and a daily oral dosage of 15 mg (range 10 mg to 50 mg). Substance Abuse The number of positive urine tests was significantly higher in the zuclopenthixol group than in the risperidone group (Table 2). All patients consumed substances during the follow-up, even though the first positive urine test occurred in the ninth week for the long-acting risperidone group (95%CI, 7 to 10) and the seventh for the zuclopenthixol group (95%CI, 5 to 8) (Longrak 2.86, df 1, P < 0.09) (Figure 1).
Psychopathology There were significant differences in the Negative and General Psychopathology PANSS subscales at the end of the study (Table 2). The percentage of subjects with a PANSS score 20% lower than that of baseline was higher in the group treated with risperidone (89% and 50%; c2 = 21.1, df 1, P < 0.0001). Compliance Patients treated with risperidone attended a significantly larger number of SAMM program sessions than those of the zuclopenthixol group. In fact, 92.9% of those in the risperidone group were classified as good compliers (Table 2). Drug Safety There was a more significant reduction in the scores on the scales for EPS and UKU (t = 1.92, P < 0.04) in the risperidone group. Antiparkinsonian drugs were used more frequently in the zuclopenthixol group (48.5% and 27%, c2 = 5.69, df 1, P < 0.01). Logistic Regression Models for Explaining the Prognosis In the model for explaining the reduction in positive urine tests, the variables involved at the end of the follow-up period were severity of dependence measured with the ASI and type of antipsychotic received during the treatment. That is, greater reduction in positive urine tests was associated with having used long-acting risperidone and with less severity of dependence. Regarding the model for explaining the reduction of the total PANSS score by > 20%, at the end of follow-up, the variables that entered the model were baseline severity of dependence measured with the ASI and type of treatment received during the study. That is, the less severe the dependence, the higher the risk of a reduction in the total PANSS score. Finally, in the model for explaining compliance with the SAMM program, the variables involved were number of hospitalizations since onset of schizophrenia, type of antipsychotic received during the study, and severity of dependence measured with the ASI. It might therefore be stated that a history of few admissions to a psychiatric hospital, using long-acting risperidone, and less severe dependence, is associated with better compliance. DiscussionThe results of this study indicate that, in subjects with schizophrenia and substance abuse, long-acting risperidone was more useful than zuclopenthixol-depot in reducing substance abuse and in alleviating symptomatology of schizophrenia. Risperidone also led to more improvement than zuclopenthixol with regard to compliance with the program for managing substance abuse. Taking into account the results of the different regression models, it can be stated that choice of antipsychotic is relevant for explaining the results related to substance abuse and schizophrenia symptoms and to compliance with the psychotherapeutic program. With regard to the reduction in substance use, the results of the present study indicate that long-acting risperidone contributes to reducing substance consumption in a consistent way, mainly in subjects with less severe dependence. Also, in a previous study (6), risperidone decreased positive urinary tests significantly more than zuclopenthixol in subjects with schizophrenia and SUDs. Smelson and others showed that individuals with schizophrenia and cocaine dependence treated with risperidone had significantly fewer cue-elicited cravings and relapses than did subjects treated with typical antipsychotics (7). Indirect evidence of the greater efficacy of risperidone can be found in other studies. Where it has been used in the treatment of subjects with psychotic disorders and opiates abuse, it has been shown that 50% of subjects reduced their use of opiates (21). Indeed, it has been speculated that this type of antipsychotic may form the basis of the principal treatment strategy for acting on negative symptoms and reducing dysphoria and extrapyramidal symptoms (5). There are several nonexclusive hypotheses that support this notion. It has been pointed out that patients diagnosed with schizophrenia tend to use substances more frequently than the general population in an attempt to reduce their states of dysphoria (22,23), the positive and negative symptoms of the disorder (22-26), and the cognitive deficits related to schizophrenia or psychoactive drugs (27) or in an attempt to increase mesocortical dopaminergic hypoactivity and alleviate the anhedonia associated with their situation (28). It is also possible that a subgroup of these patients will present greater risk owing to the presence of antisocial features or novelty seeking, modulated by the serotonergic and dopaminergic systems, respectively (5). The pharmacologic characteristics of atypical antipsychotics and, in particular, risperidone, and their actions on factors of vulnerability to substance use in this population may partly explain their efficacy (5). Moreover, outside the context of patients diagnosed with schizophrenia, it has been suggested that atypical antipsychotics may reduce the use of such substances as alcohol and cocaine (29,30). It has been hypothesized that atypical antipsychotics reduce substance use more than classic neuroleptics owing to lower hypersensitivity to D2 dopaminergic receptors in mesolimbic pathways (31,32).
In relation to the efficacy of long-lasting risperidone and zuclopenthixol-depot in reducing schizophrenia symptoms, it is not possible to compare similar studies. However, the differences between the 2 drugs in schizophrenia subjects have been pointed out elsewhere (6,13). In samples with and without dual diagnosis, risperidone and zuclopenthixol were equally effective in reducing positive, but not negative, symptomatology. The percentage response to long-acting risperidone in our study (89%) is higher than others found in those carried out in subjects with schizophrenia and SUD (72%, 6) or without SUD (61% to 74%, 33–35). However, percentage response to zuclopenthixol-depot was also higher than in other studies (44–48%; 6,13). The greater efficacy of risperidone, compared with zuclopenthixol, above all in the reduction of negative symptoms, may be explained by the different pharmacologic actions of the 2 drugs (36,37). Regarding program compliance for managing substance use, the results are better than others shown in a previous study (6). It has been suggested that one of the possible determining factors in the achievement of medium- and long-term objectives is that patients with less severe dependence find the treatment program useful and that their clinical situation allows them to comply with and accept the content of the therapeutic program (6). Thus a pharmacologic treatment such as risperidone may be more effective than classic neuroleptics in achieving compliance with the psychotherapeutic program for 2 reasons: it reduces some of the clinical factors that may predispose to the use of drugs (positive and negative symptoms), and it reduces the reinforcing capacity of drugs of abuse. Thus patients may experience a greater sense of self-efficacy as they attain partial goals, which in turn would lead to more active involvement in the program. In subjects with more severe dependence, differences between treatments could disappear owing to the substance abuse effects. In sum, there is a need for further research that would permit clinicians to approach more effectively the treatment of schizophrenia patients with dual diagnosis. It would also be of interest to determine which type of psychotherapeutic intervention is most appropriate for each type of patient and which works best in combination with the pharmacologic treatment. The results of this study should be considered in view of the limitations. We excluded 37% of the subjects in the selection period. It may well be that precisely those most severely affected, in relation to both their psychotic condition and substance abuse, were the ones who declined to participate. Further, all participants were able to be treated as outpatients, which implies that they had at least some sort of family support. Those who were homeless or with inadequate social or family support (and who constitute a group with more serious characteristics) remained outside the study. The fact that the psychiatrists who treated the patients had knowledge of their outcome may also affect the results. Funding and SupportWe received a research grant (grant number 02/2003) from the Fundación Cerebro y Mente. None of the authors received financial support from the pharmaceuticals industry. AcknowledgementsJosé María Bellón, Servicio de Medicina Preventiva (Preventive Medicine Service), Hospital Universitario Gregorio MaraZon, Madrid, for assistance in statistical methods. References1. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin FK. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area Study. JAMA 1990;264:2511–8. 2. Kavanagh DJ, McGrath J, Saunders JB, Dore G, Clark D. Substance misuse in patients with schizophrenia: epidemiology and management. Drugs 2002;62:743–55. 3. Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse and the course of recent-onset schizophrenic disorders. Arch Gen Psychiatry 1994;51:273–9. 4. Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes. Schizophr Res 1999;(Suppl 35):93–100. 5. Rubio G, Casas M. Revisión del tratamiento de la esquizofrenia en individuos con abuso de drogas. Actas Esp Psiquiatr 2001;29:124–30. 6. Rubio G, Martínez I, Ponce G, López-MuZoz F, Alamo C, Jiménez-Arriero MA, Palomo T. Risperidone versus zuclopenthixol in the treatment of schizophrenia with substance abuse comorbidity: a long-term, randomized, controlled, single-blind crossover study. Eur J Psychiatr 2006. Forthcoming. 7. Smelson DA, Losonczy MF, Davis CW, Kaune M, Williams J, Ziedonis D. Risperidone decreases craving and relapses in individuals with schizophrenia and cocaine dependence. Can J Psychiatry 2002;47:671–5. 8. Glazer WM, Kane JM. Depot neuroleptic therapy: an underutilized treatment opinion. J Clin Psychiatry 1992;53:426–33. 9. Ziedonis DM, Trudeau K. Motivation to quit using substances among individuals with schizophrenia: implications for a motivation-based treatment model. Schizophr Bull 1997;23:229–38. 10. Kane JM, Leucht S, Carpenter D, Docherty JP. The expert consensus guideline of psychotic disorders. Optimizing pharmacologic treatment of psychotic disorders. J Clin Psychiatry 2003;64 (Suppl 12):1–97. 11. Möller HJ, Llorca PM, Sacchetti E, Martin SD, Medori R, Parellada E. Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies. Int Clin Psychopharmacology 2005;20:121–30. 12. Kingstone E, Kolivakis T, Kossatz I. Double-blind study of clopenthixol and chlorpromazine in acute hospitalized schizophrenics. Int J Clin Ther Toxicol 1971;1/70:41–5. 13. Huttunen MO, Piepponen T, Rantanen H, Larmo I, Nyholm R, Raitasuo V. Risperidone versus zuclopenthixol in the treatment of acute schizophrenic episodes: a double-blind parallel-group trial. Acta Psychiatr Scand 1995;91:271-7. 14. First MB, Spitzer RL, Gibbson M, Williams BW. Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (SCID-CV). Washington (IN): American Psychiatric Press; 2001. 15. McLellan AT, Luborsky L, Woody GE, O’Brien CP. An improved diagnostic evaluation instrument for substance abuse patients: the Addiction Severity Index. J Nerv Men Dis 1980;168;26–33. 16. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale for Schizophrenia. Schizophr Bull 1987;13:261–76. 17. Guy W, editor. In: ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Rockville (MD): US Department of Health, Education and Welfare;1976. p 217–22. 18. Chouinard G, Ross-Chouinard A, Annable L, Jones BD. The Extrapyramidal Symptom Rating Scale. Can J Neurol Sci 1980;7:233. 19. Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. Acta Psychiatr Scand 1987;76(Suppl 334):81–94. 20. Roberts LJ, Shaner A, Eckman TA. Overcoming addictions. Skills training for people with schizophrenia. New York (NY): WWW Norton & Company; 1999. 21. Casas M, Gutierrez M, Gibert J, Bobes J, Roncero C, Octavio I. Risperidona en el tratamiento de pacientes psicóticos con abuso y dependencia de opiáceos. Actas Esp Psiquiatr 2001;29:380–5. 22. Buckley P, Thompson PA, Way L, Meltzer HY. Substance abuse among patients with treatment-resistant schizophrenia: cfharacteristics and implications for clozapine. Am J Psychiatry 1994;151:385–9. 23. McEvoy J, Freudenreich O, McGree M. Clozapine decreases smoking in patients with chronic schizophrenia. Biol Psychiatry 1995;37:550–2. 24. Brunette LM, Mueser KT, Xie H, Drake RE. Relationships between symptoms of schizophrenia and substance abuse. J Nerv Ment Dis 1997;185:13–20. 25. Drake RE, Xie H, McHugo GJ, Green AI. The effects of clozapine on alcohol and drug use disorders among schizophrenic patients. Schizophr Bull 2000;26:441–9. 26. Zimmet SV, Strous RD, Burgess ES, Kohnstamm S, Green AL. Effects of clozapine on substance use in patients with schizophrenia and psychoaffective disorders: a retrospective survey. J Clin Psychopharmacol 2000;20:94–8. 27. Marchi M, Raiteri M. Nicotine autoreceptors mediating enhancement of acetylcholine release become operative in conditions of impaired cholinergic presynaptic function. J Neurochem 1996;67:1974–81. 28. Green AI, Zimmer SV, Strous RD, Schilkraut JJ. Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine. Harv Rev Psychiatry 1999;6:287–96. 29. Smelson DA, Roy A, Roy M. Risperidone and neuropsychological test performance in cocaine-withdrawn patients. Can J Psychiatry 1997;42:431. 30. Newton TF, Ling W, Kalechstein A, Uslaner J, Tervo K. Risperidone pre-treatment reduces the euphoric effects of experimentally administered cocaine. Psychiatr Res 2001;102:227–33. 31. See RE, Aravagiri M, Ellison GD. Chronic neuroleptic treatment in rats produces persisting changes in GABA-A and dopamine D-2, but not dopamine D-1, receptors. Life Sci 1989;44:229–36. 32. Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 1991;41:1–24. 33. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825–35. 34. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factors analysis: combined results of the North American Trial. J Clin Psychiatry 1997;58:538–46. 35. Peuskens J. Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel group study versus haloperidol. Br J Psychiatry 1995;166:712–26. 36. Schotte A, Janssen PFM, Gommeren W, Luyten WHML, Van Gompel P, Lesage AS, and others. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 1996;124:57–73. 37. Yoshimura R, Nakamura J, Ueda N, Terao T. Effect of risperidone on plasma free 3-methoxy-4-hydroxyphenylglycol (pMHPG) levels in schizophrenic patients: relationship among plasma concentrations of risperidone and 9-hydroxyrisperidone, pMHPG levels, and clinical improvement. Int Clin Psychopharmacol 2000;15:175–80. Author(s)Manuscript received November 2005, revised, and accepted March 2006. 1. Psychiatrist, Department of Psychiatry; Assistant Professor, Complutense University, Madrid, Spain, Mental Health Services of Retiro, Madrid, Spain. 2. Psychiatrist, Mental Health Services of Retiro, Madrid, Spain. 3. Psychiatrist, Psychiatry Department, Assistant Professor, “12 de Octubre” University Hospital, Madrid, Spain. 4. Pharmacology Department, Faculty of Medicine, University of Alcalá, Madrid, Spain. 5. Assistant Professor, Pharmacology Department, Faculty of Medicine, University of Alcalá, Madrid, Spain. Address for correspondence: Dr G Rubio, Servicios de Salud Mental de Retiro, c/o Lope de Rueda, 43, 28009-Madrid, Spain e-mail: garuva@inicia.es
1 | 2
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||