by Lieuwe de Haan, Don H. hinszen, Marie E. Lenior, Evelyne Doderlein de Win, and Rob Qorsira Abstract

Transcription

1 Duration of Untreated sychosis and Outcome of Schizophrenia: Delay in Intensive sychosocial Treatment Versus Delay in Treatment With Antipsychotic Medication by Lieuwe de Haan, Don H. hinszen, Marie E. Lenior, Evelyne Doderlein de Win, and Rob Qorsira Abstract Duration of untreated psychosis (DU), defined as delay in treatment with antipsychotic medication, was found to be associated with an unfavorable course of schizophrenia. Delay in intensive psychosocial treatment (DIT) may also be related to outcome. We examined the relationship of DU and DIT with several outcome domains 6 years after onset in a cohort of 88 consecutively admitted patients with early-onset schizophrenia and related disorders. atients and their parents completed an inventory concerning DU, DIT, and various aspects of outcome. sychotic relapse during the first year after hospitalization was assessed with a chart review. Both DU and DIT were found to be associated with negative symptoms at outcome; mode of onset was not. DU was associated with mild psychotic relapse. DIT was associated with months of rehospitalization. There was no relation between DU or DIT and other aspects of outcome. When we controlled for age at onset, gender, and duration of treated first psychotic episode, only DD?T was associated with negative symptoms at outcome. DIT may be a more important predictor of negative symptoms at outcome than is delay in starting antipsychotic medication alone. Keywords: Duration of untreated psychosis, delay in psychosocial treatment, outcome, schizophrenia. Schizophrenia Bulletin, 9(): ,003. Long duration of untreated psychosis (DU) in schizophrenia has been found to be associated with longer time until remission, less remission (Loebel et al. 199), and more psychotic relapse (Crow et al. 1986). These findings remained significant when controlled for diagnosis and gender (Loebel et al. 199). Nevertheless, other studies found no association between DU and outcome (Linszen et al. 1998; Johnstone et al. 1999; Robinson et al. 1999; Craig et al. 000; de Haan et al. 000; Ho et al. 000; Hoff et al. 000; Barnes et al. 001). Moreover, DU might not be independent of other prognostic factors such as premorbid functioning, mode of onset (Haas and Sweeney 199), and prominent negative symptoms (Norman and Malla 001). In previous studies, DU was found to be related to symptom-related domains of outcome such as psychotic relapse and remission but not to other domains such as social functioning. In most of the studies, DU has been defined as the time between onset of psychotic symptoms and the start of treatment with antipsychotic medication. Besides medication, frameworks for psychiatric intervention directed at the problems of patients with a recentonset psychosis also include psychosocial interventions. Early implementation of intensive psychosocial intervention aimed at improving patients' social functioning, disease management, and self-esteem could also be an important favorable factor in the long-term prognosis. Social functioning might deteriorate if there is no early intervention directed at self-esteem and social functioning. Optimal treatment in a later stage of the illness may be hindered by increased demotivation and understimulation. The purpose of the present study is twofold. First, we wanted to know whether treatment delay defined as delay in intensive psychosocial treatment (DIT) is related to various aspects of outcome. In this study, DIT has been hypothesized to be a predictor of outcome. Second, we wondered whether DU and DIT are associated with two long-term outcome domains: psychopathology and social functioning. In short, we studied a cohort of young patients in the early phase of schizophrenia and related disorders who had completed a treatment program to Send reprint requests to Dr. L. de Haan, Academic Medical Center, University of Amsterdam, Department of sychiatry, ostbox 700, 1100 DE Amsterdam, The Netherlands; l.dehaan@amc.uva.nl. 341

2 Schizophrenia Bulletin, Vol. 9, No., 003 L. de Haan et al. determine the differential impact of two distinct operationalizations of treatment delay on several domains of long-term outcome. Methods Subjects. Included were 88 patients who were consecutively admitted to the Adolescent Clinic of the Academic Medical Center, University of Amsterdam. atients were eligible for the treatment program if they had an Axis I schizophrenic or related disorder, using DSM-III-R criteria (AA 1987). atients were referred to the program by outpatient (63%) and inpatient (37%) care facilities in the region. These care facilities were asked to refer every young patient with recent-onset schizophrenia or a related disorder to our department. The diagnosis according to DSM-III-R was made in a clinical consensus meeting (three psychiatrists and two residents) using all possible information (medical records, interviews with patients, and interviews with parents). A diagnostic reevaluation made according to the above-mentioned procedure (using DSM-IV [AA 1994]) at the last observation available (for 68 patients, this last observation was at the end of the treatment program; 0 patients had a diagnostic reevaluation in 000) showed that more patients were diagnosed as having a schizophrenic disorder and fewer with schizoaffective disorder; schizophreniform disorder; bipolar disorder, manic; and psychotic disorder not otherwise specified (table 1). Cannabis abuse was a frequently encountered comorbid disorder in the study population. At admission, 37 percent of the patients used cannabis, and 19 percent used it on a daily basis. atients with primary alcohol dependence, drug depen- Table 1. atient characteristics: diagnosis, demographic, and independent variables At admission At end of treatment program DSM-III-R, DSM-IV Axis I, n (%) 1 Schizophrenic disorder 63 (7) 74 (84) Schizoaffective disorder 1(14) 8(9) Schizophreniform disorder 6 (7) () Bipolar disorder, manic (with discongruent psychotic features) 3 (3) 1 (1) sychotic disorder not otherwise specified 4 (5) 3 (3) Gender, n (%) Female 0 (3) Male 68 (77) Marital status unmarried, n (%) 88 (100) Ethnicity, n (%) Caucasian 73 (83) Chinese () Indonesian 3 (3) Surinamese 10(11) Cannabis use, n (%) 39 (37) Cannabis use daily, n (%) (19) Age at onset of first psychotic episode, mean (SD), yrs 19 (.5) Duration of untreated psychosis, mean (SD), mos 8.6(11.4) Delay in intensive psychosocial treatment, mean (SD), mos 19 (19.0) Mode of onset, n Acute 34 Insidious 54 Time between onset of first psychotic episode and interview, mean (SD), yrs 6 (.3) Note. SD = standard deviation. ercentages do not always total 100 because of rounding. 1 DSM-III-R was used at admission and DSM-IV used at end of treatment program. 34

3 Duration of Untreated sychosis and Outcome Schizophrenia Bulletin, Vol. 9, No., 003 dence (other than cannabis), or brief drug-related psychosis were not included in the treatment program. The mean age at onset of psychotic symptoms was 19 years (standard deviation [SD].5). Table 1 contains more information on demographic and illness variables. Treatment atients took part in an intensive psychosocial and medication treatment program for young patients with recent-onset schizophrenia and related disorders in clinical, day treatment, and outpatient care facilities. The treatment involved pharmacotherapy; psychoeducation for patients and parents; an individually oriented intervention for disease management, including recognition of early prodromal signs; stress management; and medication management (Liberman et al. 1986) as well as intensive support for structural activities (work, study, etc.), continuity of care, and parent groups (Linszen et al. 1996). We focused on increasing the self-esteem of patients. The inpatient structured-milieu treatment program was aimed at remission or stabilization of psychotic symptoms. The duration of the inpatient treatment period varied with the time needed to remit or stabilize psychotic symptoms (mean duration clinical plus day treatment phase in months: 3.4; SD 1.8). The staff tried to maximize antipsychotic medication compliance. atients received group education about the nature and the treatment of the illness. Development of illness insight and the controllability of the illness with medication and active coping with stress were emphasized. The patients were given support in matters of education, employment, and finances. After the creation of a working alliance with parents and other relatives as described by Anderson et al. (1986), relatives attended psychoeducational meetings in groups of three or four families. atients did not attend these meetings. Relatives were instructed to create low stress levels for their child and were taught how to recognize positive and negative symptoms and prodromal signs of psychotic relapse. The duration of outpatient treatment was 1 year. atients were seen weekly for the first 6 weeks, every other week for the following 3 months, and then at monthly intervals. atients could be seen more frequently if necessary. atients were intensively coached in finding structured daily activities. To find the most appropriate activity, we evaluated the patient's behavior in the ward and during therapeutic sessions, and the patient's wishes and abilities. Modest target activities were deliberately chosen in order to maximize the success rate. This part of the treatment program involved frequent contact with parents, teachers, and other caregivers. Assessment: Inventory. Eighty-eight patients admitted consecutively in 1 year and their parents were sent an inventory 3 years after admission. Fifty-four patients and parents returned an inventory, the remaining 34 patients and parents were interviewed by phone, and the inventory was then used as an interview schedule. All patients and parents who were alive at the time of the followup evaluation could be reached. We did not include the parents of two patients who committed suicide. atients and parents were asked about the first onset of psychotic symptoms. sychotic symptoms were defined as (1) delusions: strange individual convictions that are not concordant with reality, for example, thought reading or paranoid delusions; () hallucinations: sensory experiences (hearing, sight, smell, etc.) without real noise, image, or odor; and (3) disorganization: verbal expressions that are strange or incomprehensible, or behavior that is strange or chaotic. atients and parents were also asked about the start of antipsychotic medication (for a minimum of 6 weeks) and the end of the first psychotic episode. By demanding a minimum duration of 6 weeks' treatment with antipsychotic medication, we tried to operationalize the start of adequate treatment with antipsychotic medication. With this definition, we calculated DU and the duration of treated first psychotic episode, which is defined as the time from the start of the treatment with antipsychotic medication until remission (comparable to the time until remission in the study of Loebel et al. 199). Before admission to our department, patients received regular psychiatric care. DIT was defined as the time between the first contact with psychiatric care relating to the first psychotic episode and the moment of admission to our specialized department. We chose the moment of first contact with psychiatric care and not the onset of psychotic symptoms as the starting point of the DIT because we wanted to create a clear distinction between DU and DIT in order to study the difference in prognostic significance of delay in treatment with antipsychotic medication versus delay in starting intensive psychosocial treatment. There was also a clinical reason for defining DIT as we did: first contact with psychiatric care offered the first possibility for intensive intervention (figure 1). The following outcome measures were used: the contemporary living situation, structural activities in hours per week (hobby, education, volunteer work, regular work), psychopathological state (positive symptoms and negative symptoms), global functioning, and the total duration of psychiatric hospitalization after the treatment program. ositive symptoms were defined as mentioned before. Negative symptoms were defined according to the ositive and Negative Syndrome Scale rating manual (Kay et al. 1987) as (1) blunted affect: diminished emotional responsiveness as characterized by a reduction in facial expression, modulation of feelings, and communicative gestures; () emotional and social withdrawal: lack of interest in, involvement with, and affective commitment to life events 343

4 Schizophrenia Bulletin, Vol. 9, No., 003 L. de Haan et al. Figure 1. Mean psychopathological and treatment episodes and timing of measurement duration in months (standard deviation) Time between onset psychosis and follow-up inventory 7 (7.6) Duration untreated sychosis 8.6 (11.4) j j I Duration of treated first I sychotic episode 17.7 (6.1)* I Delay Intensive sychosocial I Intervention 19(19.0) Duration intensive psychosocial treatment 15.6(.7) j Duration clinical and day-treatment phase 3.4 (1.8) tonset sychosis t First contact psychiatric care, start adequate antipsychotic medication t Start intensive psychosocial Intervention t Start outpatient care T End of intensive psychosocial intervention Diagnostic re-evaluation t Inventory Chart review Time in months after onset of psychosis * Most patients were in remission of their first psychotic episode at the time of start of the intensive psychosocial intervention. However, since the SD of the duration of treated first psychotic episode is extensive, some patients were not in remission at the time of the start of the intensive psychosocial intervention. Some patients suffered from a second psychotic episode at the start of the intensive psychoscocial intervention. and social interactions; (3) lack of spontaneity and flow of conversation: reduction in the normal flow of conversation associated with apathy. These items were selected because the parent who had daily contact with the patient and was aware of the problems could make these ratings. arents could describe these items thanks to their intensive psychoeducation during the program. These items can be seen as observable phenomena, and it was their observable character that made instruction possible. ositive and negative symptoms were scored by parents who had regular contact with the patient on a three-point scale according to their impact on functioning (no symptoms, mild symptoms with moderate impact on functioning, severe symptoms with severe impact on functioning). Assessment of positive and negative symptoms in three categories by treating clinicians was available for 3 patients. Kappa between assessment of parents and clinicians was 0.76 for positive symptoms and 0.7 for negative symptoms. 344

5 Duration of Untreated sychosis and Outcome Schizophrenia Bulletin, Vol. 9, No., 003 Assessment: Chart Review. At admission to our treatment program, a detailed description of the duration of the prodromal phase before onset of first psychosis was assessed. Acute onset is defined as a period of a month or less between first psychiatric symptoms and first psychotic symptoms. A careful clinical description of 1-year outpatient care after treatment in our hospital was available for all patients. Mild and severe psychotic relapses were rated over a 1-month period. Mild psychotic relapse was defined as a recurrence or exacerbation of psychotic symptoms (during no more than 1 week) for which an increase of antipsychotic medication was needed, without significant decline in social functioning. Severe psychotic relapse was defined as a recurrence or exacerbation of psychotic symptoms for which increase of medication was necessary, with a significant decline in social functioning and/or duration of more than 1 week. One of the authors (R.G.) assessed from the chart review the number of psychotic relapses and the severity of the relapse. A randomly chosen sample of 36 patients was examined independently by another author (L.d.H.). Both were blind to the DU and DIT of these patients. For one patient there was disagreement about the severity of the relapse (kappa = 0.89). Both authors reached consensus about the categories mild and severe relapse after reevaluating all charts of patients with a relapse. For another patient, the severity of the relapse was changed from mild to severe because a reexamination of this chart showed that the relapse lasted longer than 1 week. Data Analysis. Data were analyzed with the SSS package (Norusis 1990). The relations of the independent variables DU, DIT, and duration of treated first psychotic episode to outcome variables were analyzed univariately. The distribution of DU, DIT, and duration of treated first psychotic episode was skewed, prompting the use of nonparametric methods of analysis. For categorical variables the statistic is x (Kruskal-Wallis test); for continuous variables the statistic is p (Spearman's rank correlation). Subsequently, the effect of DU and DIT on the outcome measure that had a significant relationship with DU and DIT in the univariate analyses was analyzed multivariately. olytomous logistic regression analysis (Dixon et al. 1990) was used because the outcome variable had three levels. Duration of treated first psychotic episode, age at onset of psychiatric illness, and gender were included in the model. First, the interval variables were tested for nonlinear (U-shape) relations with negative symptoms (Hosmer and Lemeshow 1989). Second, interactions between the variables in the model were tested by adding these, one at a time, to the model of main effects only. Finally, the selected terms were tested for their relative contribution to the prevalence of negative symptoms. Results The mean DU was 8.6 months (SD 11.4), and the median was 3.0 months. There were no differences in DU between males and females. The mean duration of first psychotic episode was 6.3 months (SD 31.3). The mean duration of treated first psychotic episode was 17.7 months (SD 6.1). The mean DIT was 19 months (SD 19.0) and the mean number of previous hospitalizations was 1.0. The mean time between onset of psychotic symptoms and interview was 7 months (SD 7.6 months). The relations between DU, DIT, duration of treated first psychotic episode, and outcome variables are shown in table. Negative symptoms at outcome were significantly related with DIT (x = 1.1; df=\p< 0.01) and with DU (x = 6.16; df = ; p = 0.05). No association was found between DU or DIT and duration of treated first psychotic episode or positive symptoms at outcome. We also found no association between DU or DIT and the number of severe relapses during the first year after hospitalization. However, we found a relation between DU and mild relapses during the first year after hospitalization (x = 5.31; df= l;p = 0.0). DIT was related to months of hospitalization during followup (p = 0.34; p < 0.01). We found no relation between DU or DIT and social outcome. Mode of onset appeared not to be related to negative symptoms at outcome. The independent variables DU and DIT were found to be related to the severity of negative symptoms. We therefore tested the effect of these variables multivariately, together with three other prognostic factors: duration of treated first psychotic episode, age at onset of psychosis, and gender. The effects of independent variables on the severity of negative symptoms are shown in table 3. The relation of DIT to negative symptoms was found to be nonlinear. This variable was therefore dichotomized. The first half of the patients had a relatively short DIT (0-1 months); the second half had a longer delay ( months). In this analysis, DU was not significantly related to negative symptoms (p = 0.07). The odds ratios for DIT were both greater than 1.0 (p = 0.03). atients with a relatively longer DIT had a five times higher probability of mild negative symptoms and an almost 4.5 times higher probability of severe negative symptoms. Longer duration of treated first psychotic episode was related to more mild negative symptoms (odds ratio 1.30) and fewer severe negative symptoms (odds ratio 0.94). Age at onset of psychosis and gender were not related to the severity of negative symptoms. 345

6 Schizophrenia Bulletin, Vol. 9, No., 003 L. de Haan et al. Table. Relations between DU, DIT, and duration of treated first psychotic episode and outcome variables Living condition, n (%) Independent With parental family Supported living Hobby (hpw), mean (SD) Education (hpw), mean (SD) Volunteer work (hpw), mean (SD) Regular work (hpw), mean (SD) Activities, n (%) No activities Activities ositive symptoms, n (%) No Mild Severe Negative symptoms, n (%) No Mild Severe Global score, n (%) Good Intermediate oor Severe relapses, n (%) None One or more Mild relapses, n (%) None One or more Mos of hospitalization, mean (SD) (4) (3) (6) (6.1) (8.5) (7.1) (16.6) (5) (75) (66) (19) (15) (31) (38) (3) (39) (38) (4) (78) () (85) (15) (14.9) Stat DU Stat DIT < <0.01 Duration of Treated First sychotic Episode Stat < Note. DIT = delay in intensive psychosocial treatment; DU = duration of untreated psychosis; hpw = hours per week; stat. = statistic, ercentages do not always total 100 because of rounding. 1 For categorical variables the statistic is x (Kruskal-Wallis test); for continuous variables the statistic is p (Spearman's rank correlation). Discussion We found an association between DU and negative symptoms 6 years after the onset of psychosis. When we tested which variables were related to negative symptoms at outcome as we controlled for other variables, DU no longer appeared to be significantly associated with negative symptoms. atients with a longer DIT had a higher probability of negative symptoms 6 years after the start of psychotic symptoms, independent of the influence of DU, duration of treated psychosis, age at onset, and gender. These results suggest that delay in intensive psychosocial treatment may be a better predictor of negative symptoms at outcome than delay in starting antipsychotic medication alone. These results are in line with the finding of Mojtabai et al. (1998), who reported in a meta-analytic review of controlled outcome studies a relatively great effect size on negative symptoms of psychotherapy in addition to standard pharmacological treatment in schizophrenia. However, in the atient Outcomes Research Team review, no conclusive and little suggestive evidence was found for psychosocial treatment effects on negative symptoms (Lehman and Steinwachs 1998). We did not find an association between DU and duration of treated first psychotic episode. erhaps our assessment was not detailed enough to replicate the subtle difference in time until remission as found by Loebel et al. (199). Moreover, DU shorter than 1 year may not be a robust predictor of psychopathological outcome. In our study, DU appeared to be neither a predictor of social 346

7 Duration of Untreated sychosis and Outcome Schizophrenia Bulletin, Vol. 9, No., 003 Table 3. Effects of independent variables on the occurrence of negative symptoms: results of polytomous logistic regression analysis (n = 88) Mild Symptoms Severe Symptoms Likelihood Ratio Test SE OR SE OR X df DU DIT 1 Duration of first treated psychotic episode Age at onset Gender Duration of treated first psychotic episode x age of onset O.01 Note. DIT = delay in intensive psychosocial treatment; DU = duration of untreated psychosis; OR = odds ratio; SE = standard error. 1 >1 mos versus si mos. Female versus male. functioning nor a consistent predictor of psychotic symptoms and relapse. Besides the association between DIT and negative symptoms at outcome, DIT was also associated with months of hospitalization an important and objectively assessed outcome measure. The finding of an opposite direction of association between duration of treated first psychotic episode and mild and severe negative symptoms is hard to interpret. This relationship was not our primary object of study, and it may be a chance finding. In contrast to women in the cohorts of Larsen et al. (1996) and Loebel et al. (199), the women in our cohort did not have a shorter DU than men. The relatively short DU, young age, and overrepresentation of males in our study may preclude a gender difference. Ho et al. (000) also found no association between gender and DU in a group of patients that was about 60 percent men. Age at onset was not an independent predictor of negative symptoms at outcome in our study. The absence of this relation could be due to the small variation in age at onset in our patients. Ho et al. (000) found in a group with a slightly older age at onset and with a somewhat greater variation in age at onset than ours a relation between age at onset and time from onset of first general symptom to initiation of neuroleptic treatment, but not between age at onset and time from onset of full positive syndrome to initiation of neuroleptic treatment. To interpret our results, it is essential to consider the relatively short DU we found and the relatively long period after onset of psychosis we studied, compared to most other studies of the relation between DU and outcome. Limitations of our study are the retrospective design, the overrepresentation of young men, and the fact that the time from onset of first psychiatric symptom to initiation of treatment with antipsychotic drug medication is not taken into account. We supposed that onset of first psychiatric symptom was too difficult to ascertain retrospectively. We want to stress that many factors may influence treatment-seeking behaviors. These sociocultural and psychopathological factors may influence outcome in their own right, and the relationship between DIT and negative symptoms at outcome may depend on these factors. Our results suggest that delay in start of an intensive psychosocial and drug treatment directed at several outcome domains is a more important predictor of negative symptoms at long-term outcome and of months of hospitalization than delay in starting antipsychotic medication alone. However, our data do not permit us to conclude that delay in start of an intensive psychosocial intervention causes more severe negative symptoms at outcome. Indeed, more prominent negative symptoms in the early phase of the psychotic disorder might cause delay. The question of whether early implementation of intensive psychosocial intervention improves aspects of long-term outcome, independent of other prognostic factors, needs further study. References American sychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: AA, American sychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: AA,

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