Acute-phase treatment in general hospitals: clinical psychopharmacologic evaluation in first-episode schizophrenia patients

2.1. Clinical setting 

Most psychotic patients in the catchment area of eastern Tokyo (approximately 1,200,000 inhabitants) who require involuntary admission are taken to the 30-bed psychiatric ward of the Tokyo Metropolitan Bokuto General Hospital, in accordance with the 1995 Law Concerning Mental Health and Welfare for the Mentally Disabled. Therefore, patients are not selected. All patients admitted to the ward were examined qd by a psychiatrist licensed by the Ministry of Health and Welfare of Japanese Government to examine involuntarily admitted patients. This physician filled out an involuntary admissions form, which was submitted to the Governor of Tokyo. In cases of severe complications, the patient was admitted not to the psychiatric ward but to the Critical Care Center of our general hospital. Patients with severe complications were excluded from our study. The average hospital stay was approximately 50–60 days.

2.2. Clinical protocol 

Of the patients admitted during a 14-month period (July 1, 1999 to August 31, 2000), all female first-episode patients meeting the ICD-10 criteria for schizophrenia, schizotypal and delusional disorders [14] were recruited. In addition, subjects had to have a symptom severity of at least moderate on at least one of the Positive and Negative Syndrome Scale (PANSS) [15] positive symptom items. Patients who were older than 60, comorbid with alcohol or psychoactive substance abuse, or had obvious complications were excluded.

All subjects received risperidone (1 to 12 mg) as an antipsychotic and also levomepromazine (0 to 200 mg) as sedative medication, if necessary, after informed consent. Flexible doses of both drugs were used as clinically required. This treatment was consistent with standard clinical practice in Japan.

At baseline and at weekly intervals, the first author rated patients using the PANSS during the 8 weeks of this study. Baseline assessments were completed within 3 days of admission because, at admission, excessive excitement masked a lot of other symptoms. Patients’ functional impairment level was also rated using the Global Assessment of Functioning Scale (GAF) at baseline and 8 weeks.

2.3. Analyses 

Patients were considered responders if (at the end of 8 weeks) they had no rating greater than 3 on any of the PANSS positive syndrome items and the insight item (Lack of judgment and insight). Other patients were considered poor responders. Demography, clinical characteristics, and timing of response to treatment were compared between the two groups.

A t test (Welch correction, if appropriate) was used for comparisons between sequential variables. If the difference between the two standard deviations was significant, Mann–Whitney U test was used. To test for the effects of responsivity on PANSS item scores, a two- (responders and poor responders) by-nine (0–8 week time points) repeated-measures ANOVA was used. The PANSS item score at each time point was compared using a post hoc Scheffe’s test. All statistical tests were two-tailed. p-Values of less than 0.05 were regarded as statistically significant.

4.1. The predictive symptoms of treatment response at baseline in acute schizophrenic patients 

At baseline, mean scores for the items Conceptual disorganization, Negative Scale total, Blunted affect, Emotional withdrawal, Poor rapport, Passive/apathetic social withdrawal, Difficulty in abstract thinking, Stereotyped thinking, Mannerisms and posturing, Disorientation, Poor attention, Preoccupation, Active social avoidance, and Depression between the two groups were significantly different. Of these, the results of Negative Scale total, Emotional withdrawal, and Active social avoidance scores are similar to scores in a previous report in which at baseline nonresponders tended to have greater total SANS scores, and specifically greater anhedonia-asociality scores [13]. In contrast, Conceptual disorganization, Difficulty in abstract thinking, and Stereotyped thinking scores are not consistent with the findings of a previous report showing that the more responsive subjects did not differ significantly from the less responsive subjects in the thinking disturbance factor until Day 15 [10]. The Blunted affect, Passive/apathetic social withdrawal, and Poor attention results are not consistent with the finding of a previous report that at Week 4, nonresponders demonstrated greater affective flattening, alogia, avolition-apathy, or poor attention scores [13]. The Poor rapport and Mannerisms and posturing scores are similar to those in a previous report on the association between poor outcome and symptoms such as bizarre behavior, inappropriate affect, catatonia, and poor rapport [16].

Conceptual disorganization, Blunted affect, Stereotyped thinking, Negative Scale total, Poor attention, Preoccupation, Active social avoidance, and Depression scores were significantly more sensitive predictors of the treatment response than other scores. Conceptual disorganization, Blunted affect, Negative Scale total, and Preoccupation scores were the most sensitive (i.e., these mean scores were very significantly different between the two groups).

Not only the differences in mean scores, but also the maximum scores of responders, which do not overlap the minimum scores of poor responders, can be used to predict the treatment response of each patient. The maximum scores of responders were less than the minimum scores of poor responders for the items Conceptual disorganization, Poor rapport, Passive/apathetic social withdrawal, Stereotyped thinking, and Negative Scale total. Therefore, these items might be specific predictors of antipsychotic treatment response. As these items are significantly correlated, observing all of them may not be necessary. Smith et al. looked at the relative influences of symptoms, insight, and neurocognition on social adjustment in schizophrenia and schizoaffective disorder [17] and found that social behavior deficits were associated with thought disorder and neurocognitive impairments. In our study, the correlations between Conceptual disorganization as a positive syndrome item and the negative syndrome items support the findings of this previous report. Thus, Conceptual disorganization and Negative Scale total may be the most sensitive and specific predictors of antipsychotic response at baseline.

4.2. The predictive symptoms of treatment response based on the differences in the time course of clinical improvement between responders and poor responders 

The time course of clinical improvement in Delusion, Hallucinatory behavior, Excitement, Suspiciousness, Positive Scale total, Uncooperativeness, Unusual thought content, Lack of judgment and insight, and General psychopathology Scale total was significantly different between the two groups, despite the lack of significant differences at baseline. Significant change in Delusion, Suspiciousness, and Unusual thought content scores compared with those at baseline first occurred at 2, 2, and 1 week, respectively. The first two are almost consistent, but the last is not consistent, with a previous report indicating the more responsive subjects did not differ significantly from the less responsive subjects in the thinking disturbance factor until Day 15 [10]. The first significant changes (relative to baseline) occurred at 1 week and were in Excitement, Positive Scale total, Uncooperativeness, Unusual thought content, Lack of judgment and insight, and General psychopathology Scale total scores; these in conjunction with baseline predictors might be used to predict treatment response at 1 week. Furthermore, Delusion, Hallucinatory behavior, and Suspiciousness scores (which first significantly changed relative to baseline at 2 weeks) may be used to predict at 2 weeks and could be used in conjunction with baseline and 1-week predictors of treatment response. As to specificity, Excitement and Scale total of General psychopathology may be superior to other items because the minimum changes in scores of responders exceeded the maximum changes in scores of poor responders.

Thus, prediction of treatment response and time course of clinical improvement in acute schizophrenic patients within 2 weeks might be possible. If a patient shows a low Conceptual disorganization score at baseline and sufficient decrease in Excitement score within 1 week, he or she will ordinarily recover in 5 weeks or so. By contrast, a patient with a high Conceptual disorganization score at baseline and insufficient decrease in Excitement score within 1 week cannot be expected to recover within several weeks with simple medication such as risperidone or haloperidol. Therefore, changing from simple to complex psychopharmcologic agents or adding medication, i.e., shifting medication to those used in treatment-resistant patients, within 2 weeks may be a rational strategy. Rapid prescribing as long as it is done rationally is important in clinical practice.

4.3. Time course of improvement in lack of judgment and insight and the appropriate duration of hospital stay after involuntary admission of acute schizophrenic patients 

In deciding involuntary admission, lack of judgment and insight is the most important factor next to self-harm or assault on others. The finding that Lack of judgment and insight score first changed significantly in the responder group at 1 week, suggests that involuntarily admitted, acute schizophrenic patients require at least 1 week of hospital stay. The explanation might be that it takes 1 week for the sedating effect of treatment to appear (refer to the first significant change in Excitement in Table 3).

Furthermore, the finding that significant change in the Lack of judgment and insight score in the responder group occurred again at 5 weeks, suggests, from the point of view of clinical psychopharmacologic management, that approximately 5 weeks of hospital stay should be guaranteed (if needed) to all who are admitted involuntarily. In support of this recommendation, clinical improvement in Delusion and Hallucinatory behavior also follow a similar time course (Table 3). Five weeks of treatment appear to be necessary to establish an observable antipsychotic effect. Patients discharged prematurely would continue to suffer delusion and hallucination and have insufficient judgment and insight. Psychiatric wards in general hospitals should cover acute-phase patients for at least this duration, if needed.

Baldessarini noted that the response to neuroleptics occurs in two phases: rapid improvement over the first week or month, followed by slower improvement over the course of the next 3–25 weeks [18]. Osser and Patterson considered 8 weeks as an adequate trial of standard neuroleptics, assuming adequate bioavailability of the agent [19]. Marder suggests that most patients should be on antipsychotic medication at least 6 weeks [20]. However, these reports either did not distinguish responders from nonresponders or drew experience-based rather than evidence-based conclusions. The 5-week hospital stay concluded from the results of the present case-control study is shorter than stays recommended in previous reports because the 5 weeks is adequate only for good responders. For non- or poor-responders, several months might be needed before antipsychotic effects become apparent [21]. General hospitals cannot provide such prolonged treatment. So, early prediction of treatment response is valuable. On the other hand, 5 weeks for a hospital stay seems to be long when compared to periods concluded from medicoeconomic analyses of government agencies or insurance companies. However, on the clinical psychopharmacologic or scientific basis of our study, 5 weeks might be the limit (the shortest recommended hospital stay) even for good responders to antipsychotics.

Despite the small number of subjects examined, a conservative claim can be made that Conceptual disorganization, Poor rapport, Passive/apathetic social withdrawal, Stereotyped thinking, and Negative Scale total scores seemed to be specific predictors of antipsychotic response at baseline. In particular, Conceptual disorganization and Negative Scale total scores may be the most sensitive and specific predictors of antipsychotic response at baseline. On the basis of the differences in the time course of clinical improvement, Excitement may have the most predictive value of antipsychotic response in 1 week. Lack of judgment and insight score in the responder group first changed significantly at 1 week (as did the Excitement score) and changed again at 5 weeks (as did the Delusion and Hallucinatory behavior scores). These results suggest that although only 1 week is needed for a sedating effect to appear, 5 weeks are needed for a true and sufficient antipsychotic effect, even in responders. Therefore, psychiatric wards in general hospitals should treat acute-phase patients for at least this duration, if needed.