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Prodromal States in Schizophrenia
Prodromal States in Schizophrenia Wolfgang Gaebel, Michaela J~nner, Nicole Frommann, Adolf Pietzcker, Wolfgang K6pcke, Michael Linden, Peter MLiller, Franz MLiller-Spahn, and Joachim Tegeler The vulnerability-stress-coping (VSC) model is the
most influential heuristic concept in understanding the course of schizophrenia, whose prodromal status still offers unsolved conceptual and methodological issues. Improved knowledge about the prodromal phase would provide a better understanding of the developing psychopathology and psychophysiology of schizophrenia and could also be of predictive value t o attune therapeutic actions to the course of the illness more precisely. To shed more light on the characteristics of prodromal states, data from a German multicenter study on intermittent versus maintenance neuroleptic long-term treatment in schizophrenia (ANI study) were reanalyzed with respect t o the prevalence and profile, nature, time course, and predic-
p
RODROMAL SYMPTOMS in schizophrenia are part of most psychoeducational training programs nowadays. However, there are still a number of unsolved conceptual and methodological issues in prodromal symptoms, as summarized by the following questions: • Are prodromes the first symptoms of the illness or its relapse (i.e., a diluted subthreshold/subclinical form of the illness, or a person's specific reaction to the beginning/ relapsing illness) or both? • Is the pattern of prodromes individually specific and identical throughout the course of illness? • Can prodromes be understood in terms of the vulnerability-stress-coping (VSC) model? • Are prodromes specific to the illness? • What is the time course of prodromes, and are they predictive of relapse? • Can prodromes be reliably used in early intervention strategies? Some of these questions will be addressed in this
From the Department of Psychiatry, Heinrich-Heine-University, Diisseldorf," Department of Psychiatry, Free University, Berlin; Department of Psychiatry, Ernst-August- University, GOttingen; Department of Psychiatry, Park-Krankenhaus, Leipzig; Department of Medical Informatics and Biomathematics, Wilhelms-University, Miinster, Germany; and Department of Psychiatry, University Basel, Basel Switzerland. Address reprint requests to Wolfgang Gaebel, M.D., Department of Psychiatry, Heinrich-Heine- University, Rheinische Kliniken Diisseldorf, Bergische LandstraJ3e 2, D-40629 Diisseldorf. Copyright © 2000 by W.B. Saunders Company 0010-440X/00/4102-1012510.00/0 76
tive value of prodromal symptoms in impending relapse. The results demonstrate that prodromes are a category of symptoms on their own, but they share variance with other symptom domains. Treatment side effects, psychotic symptoms, dysphoric mood, and social dysfunction are all associated with prodromal states--the direction of this association, however, is still to be clarified. Prodromal symptoms are also related t o the neuroleptic treatment strategy and its relapse-preventive efficacy--findings that underscore neuroleptic maintenance medication in preventing both overt and subthreshold psychotic morbidity in schizophrenia. Copyright © 2000 by W.B, Saunders Company
article, focusing mainly on our own unpublished findings from a long-term study on early intervention strategies in schizophrenia. 1,2 THE COURSE OF SCHIZOPHRENIA Schizophrenia is a heterogeneous disorder beginning mainly between the ages of 15 and 35. In men, schizophrenia begins 3 to 4 years earlier than in women) The prodromal phase is characterized by negative symptoms, followed by depressive symptoms and a prepsychotic phase until the first psychotic episode occurs." The further course in 22% of the patients is monoepisodic without lasting impairment, and in 35%, several episodes occur with no or minimal impairment. Impairment after the first episode with subsequent exacerbations and no return to normality occurs in only 8% of cases, but in 35%, the course is characterized by an impairment increasing with each further episode and no return to normality, s It is not yet clear whether relapse prodromes resemble the initial prodromes preceding the first episode of psychos i s . 6 To answer this question would require a longitudinal prospective study in a high-risk population. The present report will mainly refer to prodromal states prior to relapse. PRODROMAL STATES AND THE VSC MODEL The VSC model is the most influential heuristic concept in understanding the development of schizophrenic relapse and illness course. 7-9 Based on this model, Zubin et alJ ° formulated the following hypotheses on the development of relapse:
ComprehensivePsychiatry,Vol. 41, No. 2, Suppl. 1 (March/April), 2000: pp 76-85
PRODROMAL STATES IN SCHIZOPHRENIA
• Relapse is an indigenous characteristic of a
subtype of schizophrenia which occurs in some patients regardless of treatment, i.e., they possess a special vulnerability which is not present in non-relapsers. • Relapse occurs only as a result of a life-event stressor. • Relapse occurs when the individual's coping ability (with or without the assistance of therapeutic intervention) no longer serves to screen out the impinging stressors, which formerly could be contained. • Some combination of the above mechanisms may interact to increase the likelihood of relapse. Hence, the course of illness seems to depend on the interaction of vulnerability factors, stressors, and protectors. Increases in either vulnerability and/or stressors or decreases in protective factors are viewed as possible sources to move the vulnerable system from a stable state of remission via intermediate and prodromal states 8 to a destabilized state of psychotic exacerbation. According to Nuechterlein, 8 "intermediate states" are characterized by the following deviant psychophysiological processes: • Processing capacity overload • Tonic autonomic hyperarousal • Deficient processing of social stimuli. Prodromal states occur when the individual vulnerability threshold is crossed by excessive internal or external stressors and, at the same time, adaptive strategies, e.g., coping or support, are not available. 4 The outcome of this complex interaction depends on the following: • Extent and duration of the stressor • Individual's perception of that stressor • Individual's ability to control and regulate dysphoric affects • Individual's coping skills • Presence of social supports • Promptness and effectiveness of psychiatric intervention. If "prodromal-type symptoms" are not effectively counteracted, the phenotypically indistinguishable "prodromal phase" may occur and develop into a full-blown relapse. Hence, prodromal symptoms may indicate an imbalance of the VSC system; identification of the underlying processes could provide better understanding of the developing psychopathology and psychophysiology of schizophrenia ll:2 and also could be of predictive value to
77
initiate therapeutic actions. Research is needed to clarify the distinction between the appearance of sporadic prodromal-type symptoms and the onset of the prodromal phase of relapse in schizophrenia. In this regard, biochemical, psychophysiological, or other markers of the prodromal phase of relapse need to be established. 4 PRODROMAL SYMPTOMS
Definitions and Descriptions The concept of prodromal symptoms in general is usually retrospective: prodromes will be identified as such only after the development of definite symptoms and signs of first manifestation or relapse. Current definitions of prodromal symptoms are given in Table 1. DSM-III-R 13 contained a description of prodromal features focusing mainly on observable behavioral changes. The list of prodromal symptoms is as follows: 1. Marked social isolation or withdrawal 2. Impairment in role functioning 3. Markedly peculiar behavior 4. Impairment in personal hygiene and grooming 5. Blunted or inappropriate affect 6. Digressive, vague, overelaborate, or circumstantial speech, or poverty of speech, or poverty of content of speech 7. Odd beliefs or magical thinking 8. Unusual perceptual experiences 9. Marked lack of initiative, interest, or energy. Because of uncertainty about their nature, specificity, and reliability of measurement, within current diagnostic systems, prodromal features of schizophrenia are not particularly mentioned. According Table 1. Definitions of Prodromal Symptoms Study Keith and Matthews (1991) 46
Definition
A heterogeneous group of behaviors temporally related to the onset of psychosis Loebel et al. (1992) 47 The time interval from onset of unusual behavioral symptoms to onset of psychotic symptoms Beiser et al. (1993) 48 The period from the first noticeable symptoms to first prominent psychotic symptoms Yung and McGorry A period of prepsychotic distur(1996) 6 bance, representing a deviation from a person's previous experience and behavior
78
to DSM-IV, 14 "prodromal symptoms are often present prior to the active phase, and residual symptoms may follow it. Some prodromal and residual symptoms are relatively mild or subthreshold forms of the positive symptoms . . . . [I]n addition to these positive-like symptoms, negative symptoms are particularly common in the prodromal and residual phases and can often be quite severe" (p. 278). The ICD-1015 acknowledges prodromes as part of the schizophrenic syndrome and describes them in a manner that they may precede the onset. However, prodromal symptoms are not explicitly listed in ICD-10 diagnostic criteria. According to clinical observations, schizophrenic decompensation develops in stages gradually o v e r t i m e . 16A7 In marker terminology, relapse prodromes would specify as episode markers, 18i.e., either psychopathological or biological symptoms and/or signs indexing the very beginning of an acute exacerbation of the illness and covarying with its course. To identify the prodromal state as a subthreshold psychopathological syndrome, it is necessary to differentiate between general/unspecific, more specific/prepsychotic prodromal, and elaborated psychotic symptoms. There is debate as to whether it is methodologically possible and clinically useful to differentiate between these kinds of symptoms. 6,19 As yet, it is not definitely clear whether nonspecific/general symptoms always occur prior to more specific symptoms or whether as Malla and Norman 19 suggested--unspecific symptoms, like anxiety, may actually be reactions to early but hidden psychotic symptoms. Therefore, it would be important to assess specific and unspecific symptoms. It may be of practical value to detect more specific symptoms indicative of the onset of a psychotic episode, because generalized symptoms may depend on or are influenced by several factors other than impending exacerbation. 4
Measurement For the assessment of prodromal symptoms, a number of instruments have been developed. Some instruments, such as the Frankfurt Complaint Questionnaire, 2° e.g., were not specifically developed for monitoring prodromal symptoms, whereas others, like the Instrument for the Retrospective Assessment of Onset and Early Course of Schizophrenia, 21 were specifically designed to record the
GAEBEL ET AL
beginning and initial prodromes of schizophrenia. On the other hand, the Early Signs Scale 22 or the Early Signs Questionnaire (ESQ) 23 were developed for the assessment of relapse prodromes on the basis of systematic studies in large samples of patients and family informants. However, these retrospective studies and their instruments suffer from methodological difficulties like "effort after meaning" or the "degree of sealing over. ''6
Symptom Prevalence and Profile To elucidate the relationship of prodromal symptoms and the onset of a psychotic relapse, data from a German multicenter study on intermittent versus maintenance neuroleptic long-term treatment in schizophrenia (ANI Study l) were reanalyzed with respect to the prevalence and profile, nature, time course, and predictive value of prodromal symptoms in schizophrenic relapse (see also Gaebel et
al.2). The German Neuroleptic Treatment Study (ANI) group was established between 1980 and 1983 and developed the project design of the present study concerned with the early-intervention treatment approach. The ANI Study lasted from 1983 to 1989 with an observation phase of 2 years. The main aim of the study was to demonstrate whether this approach was feasible and effective using a broad spectrum of target measures in a large patient sample. Contrary to other studies on intermittent treatment, a specially designed control strategy was included to evaluate the relapse-predictive validity of prodromal symptoms. Three randomly assigned open neuroleptic treatments (with conventional neuroleptics) were compared in 364 schizophrenic outpatients (ICD-9, 24 and Research Diagnostic Criteria 25) after informed consent: standard prophylactic maintenance medication, and 2 types of intermittent treatment (early intervention and neuroleptic crisis intervention). The frequency of contacts was initially a minimum of once in 2 weeks (if necessary, even more frequently), but could be later reduced to once in 4 weeks in case of stable clinical conditions. Treatment decisions within a particular strategy were based on clinical assessment according to defined psychopathological and psychosocial criteria. The Brief Psychiatric Rating Scale (BPRS) was used to measure changes in psychopathology, the Global Assessment Scale (GAS) was used to measure changes in psychosocial adjustment related to symptomatology, and the CGI was used to
PRODROMAL STATES IN SCHIZOPHRENIA
79
Table 2. Prevalence of General Prodromes (%) All Patients B e f o r e Therapy (n - 1 5 8 )
Prodrome Depression Trouble concentrating Trouble sleeping Tense and nervous Restlessness Loss of interest
Maintenance Treatment (n = 70)
Intermittent Treatment (n = 88)
Differences Between Treatment Strategies(P)*
30 34 19 18 19 24
31 28 31 27 24 18
NS .0001 .0001 .0001 .0001 .0001
49 75 83 71 79 56
*Chi-square test.
measure changes in the degree of illness severity. Relapse, in particular, was clinically defined as a psychotic deterioration of maximum intensity usually demanding hospitalization, but in addition by certain minimum change scores on the indicated instruments. Although relapse rates were significantly lower under early intervention (49%) than under crisis intervention (63%), those under maintenance treatment were by far the lowest (23%). Dropout and rehospitalization rates under both intermittent treatment strategies were also significantly less favorable than under maintenance treatment, whereas psychopathology, social adjustment, subjective wellbeing, and side effects were not significantly different between treatment strategies. Cumulative neuroleptic dosage was significantly lower under intermittent treatment, even when inpatient treatment in case of rehospitalization was considered. The prodromal scale was adapted from the Early Symptom Questionnaire (ESQ), 23 and the items are listed in Tables 3 to 5. Prodromal symptoms were classified into 6 general (unspecific) prodromes which had to be rated at each contact, and an additional 3 optional prodromes which could be selected from a list of 16 symptoms consisting of unspecific and specific prodromes as well as from individual items. (It may be seen as a methodological limitation that only 3 additional prodromal
symptoms were selected, rendering the description of prodromal symptomatology incomplete.) Besides the presence of prodromes, their severity could be recorded by a scale ranging from 0 = not existing, over 1 = slight, 2 = moderate, to 3 = severe. Thus, a score for severity could be computed for each patient for each assessment (general prodromes: unweighted sum of 6 items, min = 0, max = 18). The sample consisted of 158 schizophrenic patients who completed the observation phase of the study. The mean age (mean ___SD) of the 67 male and 91 female patients was 35 --- 9.1 years. The prevalence rates of prodromes for all patients at the beginning of the study and during the 2-year treatment phase are shown in Tables 2, 3, and 4. Remarkably, the frequencies of general prodromes assessed at the beginning of the study-besides depression--were significantly higher than throughout the study phase (Table 2). These figures are in the same range as the frequencies of general symptoms reported by Herz and Melville 23 from their retrospective assessments. The same trend holds true for the additional unspecific (Table 4) and specific (Table 3) prodromes, the low prevalence rates being partly explained by the method of recording the additional prodromes (already described). The ratings at the beginning of the study
Table 3. Prevalence of Additional Specific Prodromes (%) Prodrome Feeling of being controlled Feeling of being laughed at or being watched Hallucinations (visual, acoustic) Fear of going crazy Acoustic sensitivity More religious thinking Incoherence Bad dreams *Chi-square test.
All Patients Before Maintenance Therapy (n = 158) Treatment(n ~ 70) 6 11 6 4 4 5 4 2
1,9 1.4 1.8 1.2 0.4 0.9 0.3 0.1
Intermittent Treatment(n = 88)
Differences Between TreatmentStrategies (P)*
3.1 3.2 1.8 1.0 1.8 1,1 1.2 0.6
NS .0001 NS NS .0001 NS .0001 .0001
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GAEBEL ET AL
Table 4. Prevalence of Additional Unspecific Prodromes (%) Prodrome Social withdrawal Loss of happiness Loss of appetite Loss of interest Forgetfulness Feeling worthless Feeling bad for no reason Loss of hygiene
All Patients B e f o r e Therapy (n = 1 5 8 )
Maintenance Treatment (n = 70)
Intermittent Treatment (n = 88)
DifferencesBetween Treatment Strategies (P)*
12 2 7 2 2 2 2
3.2 0.8 1.0 1.6 0.4 0.3 0.4
3.2 0.5 1.0 0.5 0.6 0.6 0.4
NS NS NS .0001 NS NS NS
1
0.5
0.4
NS
*Chi-square test.
were retrospective, asking patients and their families how their previous episode had begun. Obviously, the prevalence of prodromes assessed retrospectively-after a relapse has occurred--yields higher rates compared with prospective assessment, possibly due to the methodological influences described before. Remarkably, the prevalence of general as well as additional specific and unspecific prodromes seems to depend on the treatment strategy. The prevalence of all general prodromes is significantly different between treatment strategies, except for depression. Whereas trouble concentrating and loss of interest prevail under maintenance treatment, trouble sleeping, being tense and nervous, and restlessness prevail under intermittent treatment. Both additional unspecific (Table 4) and specific (Table 3) prodromes occur more frequently under intermittent treatment---especially feelings of being controlled, feelings of being laughed at or being watched, acoustic sensitivity, incoherence, and bad dreams---except loss of interest, for which it is the reverse. This consistently specific pattern of prodromes in the different treatment strategies may be interpreted as follows. Under intermittent treatment, still-unspecific prepsychotic (trouble sleeping, being tense and nervous, and restlessness) as well as already specific prepsychotic symptoms seem to prevail--indicating a higher proportion of time spent in prodromal states according to the significantly higher relapse rate under this treatment. Under maintenance treatment, on the contrary, prodromes are less prevalent in concordance with the lower relapse rate. However, trouble concentrating and loss of interest, both showing a higher prevalence under this treatment strategy, may be seen as neuroleptic side effects. This interpretation is corroborated by the fact that under maintenance treatment patients were subjected to
significantly higher cumulative neuroleptic dosages as compared with intermittent treatment.
Nature of Prodromal Symptoms To further elucidate the nature of prodromal states, the relationship between general prodromal symptoms (sum score) and psychopathology, neuroleptic side effects, and social functioning was analyzed (Fig 1). All correlations (Pearson's product-moment correlations) were computed for the same time of assessment throughout the study phase. Prodromes are a category of symptoms on their own, but they share variance with the different areas, ranging from 4% (Extrapyramidal Symptom Scale; EPS) to 30% (BPRS subscore schizophrenia). Interestingly, side effects partly overlap with prodromes (Dosage Record and Treatment Emergent Symptom Scale; DOTES 19%), better social adjustment is associated with less pronounced prodromes (GAS 23%), and of the 3 psychopathological syndromes of the BPRS besides schizophrenic symptomatology, anxiety-depression (26%) shows greater overlap than anergia (6%). Marder et
~
~
,a~ilnsTEa Al..... l nificS~a resig nt
Fig 1. Pearson's product correlation coefficients between score of general prodromes and other domains.
PRODROMAL STATES IN SCHIZOPHRENIA
81
2, ...............................................................................................................
~
1,
E
!1 s
I 0,,"
1 2 3 4 5 6 7 8 9 101112131415161718192021222324
Month after beginning of the study Fig 2.
l i m e course of the mean general prodromal score.
al. 26 have also reported on the (limited) prodromal significance of the BPRS anxiety-depression cluster. Altogether, these findings indicate that treatment side effects, dysphoric mood (related to side effects?), and social dysfunction seem to be associated with prodromal states--the direction of this association, however, is still to be clarified. Prodromal symptoms are not independent of the neuroleptic treatment strategy and correlate significantly with psychopharmacological side effects without being completely explained by them--findings which are in line with the results of Jolley et al. 27 concerning the superiority of continuous neuroleptic medication in preventing both psychotic and dysphoric morbidity in schizophrenia. Illness Course and Predictive Validity The course of the mean prodromal score during the 2 years of observation for all patients is shown in Fig 2. It is an irregular course, with a slight increase within the second half of the study. Taking into account the possible maximal value of 18 points, the average is on a very low level. It must be taken into account that the mean prodromal score refers to the whole sample, not differentiating
between the occurrence of relapse, time of relapse, or treatment strategy. If one wishes to examine the power and time window for prodromes in predicting the clinical course, correlations between prodromes and psychotic syndromes should be calculated for varying time intervals throughout the illness course. As already shown, correlations between general prodromes and the BPRS schizophrenia subscore at the same time of assessment amounted to an r value of .55, explaining 30% of the variance, a moderate level of "predictive" power. It can be expected that with successively increasing time intervals, correlations between prodromes and symptoms will decrease. To elucidate the influence of the time interval, we combined a fixed measurement of symptoms at different points of the course with time-lagged measurements of prodromes. The considered time window had a length of 4 weeks and was 3 times backward-shifted. Results of these analyses are shown in Table 5 and Fig 3. In concordance with expectations, correlations between general prodromes and the 3 psychopathological syndromes decrease with increasing time intervals. Associations between prodromes and the BPRS anxiety-depression factors are strongest for all BPRS subscores. However, although systematic measurements within the 4-week period are missing, it may be expected from Fig 3 that more powerful predictions could be made within this 4-week time window. In accordance with the literature, the main prodromal changes occur within 4 weeks prior to a relapse, =2,23,28probably maximizing correlations between psychopathology and prodromal symptoms during this phase. This analysis did not yet take into account whether the simultaneous correlations between prodromes and psychopathology as shown in Table 5 and Fig 1 remain stable or differ between 3 main phases of the illness course: baseline (remitted) phase, prodromal phase, and relapse phase. For further analysis, these phases were defined as follows: baseline phase,
Table 5. Correlations Between Score of General Prodromes and BPRS Syndromes for Different Intervals of l i m e Score of Prodromes 2-3 Months Before
1-2 Months Before
0-4 Weeks Before
r
No.
r
No.
r
No.
r
No.
Schizophrenia
.17
3,094
.24
3,168
.24
2,568
.55
4,256
Anxiety/depression
.28
3,095
.32
3,169
.29
2,569
.51
4,257
Anergia
.16
3,095
.17
3,169
.17
2,569
.25
4,257
BPRS Subscore
NOTE. All correlations are significant (Pearson's product correlation coefficient).
At the Same "rime
82
GAEBEL ET A L
0.6 -
0,5
- B P R S - S u b s c o r e Anxiety/Depression B P R S - S u b s c o r e Schizophrenia ~_ B PRS-Subsc___ore Anergie_ _ _
I I J
0,4
0,3
-*ill
0,1
0
2 - 3 months before
1 - 2 months before
0 - 4 weeks before
first 6 months of the study, excluding relapsing patients during the first year; prodromal phase, 3 months prior to a relapse; and relapse phase, according to predefined relapse criteria.l This differentiation allows for answering the question of the stability of simultaneous correlations according to Table 5 for different phases of the illness course. As follows from Table 6, the correlations during the baseline and prodromal phase are mainly preserved, whereas those during the relapse phase decrease dramatically. It should be mentioned that the differences between phases do not depend on the different number of observations. During the baseline, we have about 6 observations per patient, during the prodromal phase, we have about 3 observations per patient, and during relapse, we have only 1 observation per patient. By analyzing only 1 observation per patient of each phase, the correlations do not change. It may be assumed that prodromal symptoms are associates of psychopathology up to a certain severity and, as such, are predictors of relapse, but in the case of relapse, they either may not linearly increase with symptomatology or may be indistinguishable from very pronounced psychotic symptoms. But it must also be taken into consideration that the correlations were computed for all relapsing patients irrespective of the existence of a
at the same time
Fig 3. Correlations between score of general prodromes and BPRS syndromes for different intervals of time (Pearson's product correlation coefficient).
prodromal phase. It may thus be possible that prodromes as a "personalized relapse signature ''29 would have correlated more strongly with psychopathology if cases without prodromal states were excluded.
Relationship to Relapse Not only may prodromal states occur without a following exacerbation, but relapses may also develop without a preceding prodromal state. Marder et al., 3° in patients under maintenance treatment with depot neuroleptics, observed a prodromal state preceding 37% of relapses, but in 52%, a prodromal phase was not followed by a psychotic exacerbation. The prevalence of relapses preceded by nonpsychotic prodromal signs reported by Jolley et al. 27 was 53%. Within our sample, 41% of all patients failed to show prodromal symptoms during the 3 months before a relapse occurred. The relapse predictive validity of prodromal symptoms has been assessed in a number of studies, including o u r o w n . 19,28-32 A sensitivity of 8% to 81% and a specificity of 70% to 93% has been f o u n d , 33 with our own findings being at the lower end of the range: especially in the nonintervention group (crisis intervention), sensitivity was 10% and specificity 93%. With a corresponding
Table 6. Correlations Between Score of General Prodromes and BPRS Syndromes During Different Phases of Illness Course Baseline BPRS Subscore
Prodromal Phase
Relapse
r
No.
P
r
No.
P
•
No.
P
Schizophrenia
.53
722
.0001
.44
227
.0001
.23
74
.04
Anxiety/depression
.56
722
.0001
.56
227
.0001
.34
74
.002
Anergia
.29
722
.0001
.26
227
.0001
.04
74
.7
NOTE. Pearson's product correlation coefficients are shown.
PRODROMAL STATES IN SCHIZOPHRENIA
positive predictive value of 43%, it becomes clear that relapse prediction from prodromal symptoms is no better than by chance, whereas a negative predictive value of 67% demonstrates that indeed no prodromal symptoms are more often followed by nonrelapse. However, in accordance with this reasoning, it could be shown that the "hit" rate of correctly predicted relapses depended on the time interval between prodrome and relapse: predictions, on average, 2 weeks before a relapse were successful, whereas those more than 3 weeks before were not. Consequently, the monitoring of prodromes should occur at least every 2 weeks.
Early Intervention Strategies For a long time, research has focused on the development of predictors of relapse in individual patients to restrict treatment to only those patients who obviously need it. Since demographic, clinical, and biological variables are of only limited usefulness in this respect, 34 an alternative approach has been adopted. On the basis of early reports on unspecific prodromal symptoms preceding a relapse, 23 the rationale of early-intervention, timelimited, targeted neuroleptic treatment was developed. Contrary to earlier positive findings in selected patients, 35-38 however, all recently completed controlled 2-year studies on early-intervention treatment have not confirmed this strategy to be as effective as maintenance treatment in preventing relapse. 3942 Even those studies applying early neuroleptic intervention within an enriched psychosocial program 39-42 did not consistently lead to better outcome compared with those that did not. 4° Our own study 1 similarly led to disappointing results, although the early-intervention strategy based on prodromal symptoms was more favorable than the crisis intervention. Moreover, as a recent reanalysis demonstrates, first-episode patients seem to profit most from early intervention but less from maintenance treatment as compared with multiple-episode patients. These findings need replication. CONCLUSIONS
The rationale of intermittent treatment is based on the assumption that relapse is an episodic phenomenon in stabilized schizophrenics, that prodromal symptoms are valid predictors of relapse, and that impending relapse can be prevented by early neuroleptic intervention. Concerning the possible reasons for the failure to correctly predict
83
relapse particularly under crisis intervention2--a control strategy specially chosen to empirically test the predictive validity of prodromal s y m p t o m s - methodological problems may have obscured the correct and timely determination of the onset of psychosis. For instance, the wrong symptoms may have been chosen as potential predictors, i.e., the symptoms collected by Herz and Melville 23 by expost-information may have simply been subject to a "hindsight bias" of the patients and their families. In fact, the studies by Marder et al., 26 JohnstonCronk et al., 43 and Marder et al. 3° also failed to demonstrate their predictive validity. Symptoms assessed in other studies either have not been made explicit or are doubtful regarding their prodromal status. We, for instance, kept strictly to nonspecific, i.e., nonpsychotic, symptoms, which might explain their predictive failure. Because certain prodromal symptoms seem nosologically unspecific, 44 their relationship to schizophrenic relapse may not be as consistent as required for reliable prediction. In conclusion, taking together the presently available results from all controlled 2-year intermittent treatment studies, including our own, the application of this treatment of this treatment strategy cannot be generally recommended. A greater burden on the patients and their families, 41 greater demands on treatment facilities, restricted feasibility, as well as overall poorer results contribute to this conclusion. Even though all target measures besides relapse do not show any significant differences, we still consider relapse a serious event in patients' lives that should be prevented. From the perspective of maintenance treatment, which was correctly hypothesized to be the superior treatment in this respect, there seems to be no greater harm to the patients compared with intermittent treatment--at least over the observed p e r i o d - concerning social adjustment, subjective wellbeing, or side effects, despite higher cumulative dosages. On the other hand, from the perspective of early intervention, there seems to be no particular benefit. According to beneficial experiences in individual cases, however, this approach is still the only possible way to identify patients who do not need continuous treatment. Since treatment failure is not necessarily followed by rehospitalization, early-intervention treatment should be encouraged in selected cases where patients themselves will accept the risk for specified individual reasons. In
84
GAEBEL ET AL
accordance with clinical guidelines for selection of these patients, 45 stable remission seems to be the most important prerequisite; additionally, patient cooperativeness, integrative coping behavior, supportive environment, and continuously available outpatient services are facilitating conditions for an early-intervention trial. Prodromal s y m p t o m s hence could be a clue to better understand the clinical d e v e l o p m e n t and pathophysiology of illness manifestation and relapse. W h e t h e r they reflect vulnerability, stress reactivity, coping effort, or all of these c o m b i n e d is still u n k n o w n . Remarkably, a sizable n u m b e r of patients do not present with prodromes before r e l a p s e - - a finding which m u s t be a c c o m m o d a t e d b y any theory linking them to the VSC m o d e l and to relapse. Their relationship with clinical psychopathology is obvious from our data however, correlations m a y be clinically m e a n i n g f u l to use for prediction only within a narrower time w i n d o w of 2 weeks. O n the other hand, the closer to relapse prodromes are assessed, the lower the correlations with psychopathology will b e - - a paradox which
m a y either be methodologically explained or reflect a n o n l i n e a r relationship b e t w e e n the 2 domains. The different prevalence rates of prodromes under m a i n t e n a n c e a n d intermittent treatment strategies m a y be understood as an indirect argument for their relapse connotation, although their direct predictive value seems q u e s t i o n a b l e - - a t least u n d e r the methodological constraints of the studies. Moderate correlations with neuroleptic side effects, on the other hand, point to the fact that prodromes have different sources of origin which should be considered from a conceptual and methodological perspective. In summary, future research should clarify the nature o f prodromal symptoms, especially with respect to the V S C model, their unbiased recognition, their relationship with relapse, and the question of the stability of initial and relapse prodromes. W h e t h e r first-episode patients, in particular, profit from a trial with prodrome-guided early-intervention strategies should be the focus of u p c o m i n g research.
REFERENCES
1. Pietzker A, Gaebel W, Krpcke W, Linden M, MUller P, Mtiller-Spahn F, et al. Intermittent vs maintenance neuroleptic long-term treatment in schizophrenia--two-year results of a German multicenter study. J Psychiatr Res 1993;27:321-339. 2. Gaebel W, Frick U, K0pcke W, Linden M, Miiller P, Miiller-Spalm F, et al. Early neuroleptic intervention in schizophrehia: are prodromal symptoms valid predictors of relapse? Br J Psychiatry 1993;163:8-12. 3. Hafner H, an der Heiden W. Epidemiology of schizophrenia. Can J Psychiatry 1997;42:139-151. 4. H~fner H, Maurer K, Li~ffler W, an der Heiden W, Munk-J0rgensen P, Hambrecht M, et al. The ABC Schizophrenia Study: a preliminary overview of the results. Soc Psychol Psychiatr Epidemiol 1998;33:380-386. 5. Shepherd M, Watt D, Falloon I. The natural history of schizophrenia: a five-year follow-up study of outcome and prediction in a representative sample of schizophrenics. Psychol Med 1989;15:1-46. 6. Yung AR, McGorry PD. The prodromal phase of firstepisode psychosis: past and current conceptualisations.Schizophr Bull 1996;22:353-370. 7. Zubin J, Spring B. Vulnerability--a new view of schizophrenia. J Abnorm Psychol 1977;86:103-126. 8. Nuechterlein K. Vulnerability models for schizophrenia: state of the art. In: H~ifnerHG, Janzarik W (eds): Search for the Causes of Schizophrenia. Berlin, Germany: Springer, 1997:297316. 9. Clements K, Turpin G. Vulnerability models and schizophrenia: the assessment and prediction of relapse. In: Birchwood M, Tarrier N (eds): Innovations in the Psychological Management of Schizophrenia. Chichester, UK: Wiley, 1992.
10. Zubin J, Steinhauer SR, Condray R. Vulnerability to relapse in schizophrenia. Br J Psychiatry 1992;161:13-18. 11. DeLisi LE, Crow TJ, Hirsch SR. The Third Biannual Winter Workshop of Schizophrenia. Arch Gen Psychiatry 1986; 43:706-711. 12. Huber G, Gross G. The concept of basic symptoms in schizophrenia and schizoaffective psychoses. Recenti Prog Med 1989;80:648-652. 13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Ed. 3. Rev. Washington, DC: American Psychiatric Press, 1987. 14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Ed. 4. Washington, DC: American Psychiatric Press, 1994. 15. World Health Organization. Manual of the International Classification of Disease, Injuries, and Causes of Death. Rev. 10. Geneva, Switzerland: The Organization, 1994. 16. Donlon PT, Blacker KH. Stages of schizophrenic decompensation and reintegration. J Nerv Ment Dis 1973;157:200209. 17. Docherty JP, Van Kammen DP, Sifts SG, Marder SR. Stages of onset of schizophrenic psychoses. Am J Psychiatry 1978;135:420-426. 18. Nuechterlein KH, Dawson ME, Green ME Informationprocessing abnormalities as neuropsychological vulnerability indicators for schizophrenia. Acta Psychiatr Scand 1994; 89:71-79. 19. Malla AK, Norman RMG. Prodromal symptoms in schizophrenia: a prospective investigation. Br J Psychiatry 1994;164:487-493. 20. Stillwold L. Frankfurter Beschwerde Fragebogen FBF;
PRODROMAL STATES IN SCHIZOPHRENIA
Symptome Schizophrener Erkrankungen. Berlin, Germany: Springer, 1977. 21. Hafner H, Riecher-Rrssler A, Hambrecht M, Maurer K, Meissner S, Schmidtke A, et al. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophr Res 1992;6:209-223. 22. Birchwood M, Smith J, MacMillan F, Hogg B, Prasad R, Harvey C, et al. Predicting relapse in schizophrenia: the development and implementation of an early signs monitoring system using patients and families as observers, a preliminary investigation. Psychol Med 1989; 19:649-656. 23. Herz MI, Melville C. Relapse in schizophrenia. Am J Psychiatry 1980;137:801-805. 24. World Health Organization. Mental Disorders: Glossary and Guide to Their Classification in Accordance With the Ninth Revision of the International Classification of Diseases. Geneva, Switzerland: World Health Organization, 1978. 25. Spitzer RL, Endicott J, Robins E. Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. Biometrics Research. Ed. 3. New York, NY: New York State Psychiatric Institute, 1978. 26. Marder SR, Mintz J, Van Putten T, Lebell W, Wirshing WC, Johnston-Cronk K. Early prediction of relapse in schizophrenia: an application of Receiver Operating Characteristics (ROC) methods. Psychopharmacol Bull 1991;27:79-82. 27. Jolley AG, Hirsch SR, Morrison E, McRink A, Wilson L. Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years. BMJ 1990;301:837-990. 28. Tarrier N, Barrowclough C, Bamrrah JS. Prodromal signs of relapse in schizophrenia. Soc Psychol Psychiatr Epidemiol 1991 ;97:405 -412. 29. Birchwood M. Early intervention in schizophrenia: theoretical background and clinical strategies. Br J Clin Psychol 1992;31:257-278. 30. Marder SR, Wirshing WC, Van Putten T, Mintz J, McKenzie J, Johnston-Cronk K, et al. Fluphenazine v. placebo supplementation for prodromal signs of relapse in schizophrenia. Arch Gen Psychiatry 1994;51:280-287. 31. Subotnick KL, Nuechterlein KH. Prodromal signs and symptoms in schizophrenic relapse. J Abnorm Psychol 1988;97: 405-412. 32. Hirsch SR, Jolley AG. The dysphoric syndrome in schizophrenia and its implications for relapse. Br J Psychiatry 1989;155:46-50. 33. JOrgensen P. Early signs of psychotic relapse in schizophrenia. Br J Psychiatry 1998;172:327-330. 34. Gaebel W, Awad AG (eds). Prediction of Neuroleptic
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Treatment Outcome in Schizophrenia. Berlin, Germany: Springer Verlag, 1994. 35. Herz MI, Szymanski HV, Simon JC. Intermittent medication for stable schizophrenic outpatients: an alternative to maintenance medication. Am J Psychiatry 1982;139:918-922. 36. Carpenter WT, Stephens JH, Rey AC, Hanlon TE, Heinrichs DW. Early intervention vs. continuous pharmacotherapy of schizophrenia. Psychopharmacol Bull 1982;18:2123. 37. Carpenter WT, Heiurichs DW, Hanlon TE. A comparative trial of pharmacologic strategies in schizophrenia. Am J Psychiatry 1987;144:1466-1470. 38. Carpenter WT, Heinrichs DW. Early intervention, timelimited, targeted pharmacotherapy of schizophrenia. Schizophr Bull 1983;9:533-542. 39. Carpenter WT, Hanlon TE, Heinrichs DW, Summerfelt AT, Kirkpatrick B, Levine J, et al. Continuous versus targeted medication in schizophrenic outpatients: outcome results. Am J Psychiatry 1990;147:1138-1148. 40. Jolley AG, Hirsch SR, Morrison E, McRink A, Wilson L. Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years. BMJ 1990;301:837-842. 41. Herz MI, Glazer WM, Mostert MA, Sheard MA, Szymanski HV, Hafez H, et al. Intermittent vs maintenance medication in schizophrenia. Two-year results. Arch Gen Psychiatry 1991; 48:333-339. 42. Schooler NR, Keith SJ, Severe JB. Relapse and rehospitalisation during maintenance treatment of schizophrenia. Arch Gen Psychiatry 1997;54:453-463. 43. Johnston-Cronk K, Marder SR, Wirshing WC, Mintz J, McKenzie T, VanPutten T, et al. Prediction of schizophrenic relapse using prodromal symptoms. Schizophr Res 1993;9:259. 44. Fava GA, Kellner R. Prodromal symptoms in affective disorders. Am J Psychiatry 1991;148:823-830. 45. Chiles JA, Sterchi D, Hyde T, Herz MI. Intermittent medication for schizophrenic outpatients: who is eligible? Schizophr Bull 1989;15:117-121. 46. Keith SJ, Matthews SM. The diagnosis of schizophrenia: a review of onset and duration issues. Schizophr Bull 1991;17: 51-67. 47. Loebel AD, Lieberman JA, Alvir JM, Mayerhoff DI, Geisler SH, Szymanski SR. Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 1992;149:11831188. 48. Beiser M, Erickson D, Fleming JA, Iacono WG. Establishing the onset of psychotic illness. Am J Psychiatry 1993;150: 1349-1354.
most influential heuristic concept in understanding the course of schizophrenia, whose prodromal status still offers unsolved conceptual and methodological issues. Improved knowledge about the prodromal phase would provide a better understanding of the developing psychopathology and psychophysiology of schizophrenia and could also be of predictive value t o attune therapeutic actions to the course of the illness more precisely. To shed more light on the characteristics of prodromal states, data from a German multicenter study on intermittent versus maintenance neuroleptic long-term treatment in schizophrenia (ANI study) were reanalyzed with respect t o the prevalence and profile, nature, time course, and predic-
p
RODROMAL SYMPTOMS in schizophrenia are part of most psychoeducational training programs nowadays. However, there are still a number of unsolved conceptual and methodological issues in prodromal symptoms, as summarized by the following questions: • Are prodromes the first symptoms of the illness or its relapse (i.e., a diluted subthreshold/subclinical form of the illness, or a person's specific reaction to the beginning/ relapsing illness) or both? • Is the pattern of prodromes individually specific and identical throughout the course of illness? • Can prodromes be understood in terms of the vulnerability-stress-coping (VSC) model? • Are prodromes specific to the illness? • What is the time course of prodromes, and are they predictive of relapse? • Can prodromes be reliably used in early intervention strategies? Some of these questions will be addressed in this
From the Department of Psychiatry, Heinrich-Heine-University, Diisseldorf," Department of Psychiatry, Free University, Berlin; Department of Psychiatry, Ernst-August- University, GOttingen; Department of Psychiatry, Park-Krankenhaus, Leipzig; Department of Medical Informatics and Biomathematics, Wilhelms-University, Miinster, Germany; and Department of Psychiatry, University Basel, Basel Switzerland. Address reprint requests to Wolfgang Gaebel, M.D., Department of Psychiatry, Heinrich-Heine- University, Rheinische Kliniken Diisseldorf, Bergische LandstraJ3e 2, D-40629 Diisseldorf. Copyright © 2000 by W.B. Saunders Company 0010-440X/00/4102-1012510.00/0 76
tive value of prodromal symptoms in impending relapse. The results demonstrate that prodromes are a category of symptoms on their own, but they share variance with other symptom domains. Treatment side effects, psychotic symptoms, dysphoric mood, and social dysfunction are all associated with prodromal states--the direction of this association, however, is still to be clarified. Prodromal symptoms are also related t o the neuroleptic treatment strategy and its relapse-preventive efficacy--findings that underscore neuroleptic maintenance medication in preventing both overt and subthreshold psychotic morbidity in schizophrenia. Copyright © 2000 by W.B, Saunders Company
article, focusing mainly on our own unpublished findings from a long-term study on early intervention strategies in schizophrenia. 1,2 THE COURSE OF SCHIZOPHRENIA Schizophrenia is a heterogeneous disorder beginning mainly between the ages of 15 and 35. In men, schizophrenia begins 3 to 4 years earlier than in women) The prodromal phase is characterized by negative symptoms, followed by depressive symptoms and a prepsychotic phase until the first psychotic episode occurs." The further course in 22% of the patients is monoepisodic without lasting impairment, and in 35%, several episodes occur with no or minimal impairment. Impairment after the first episode with subsequent exacerbations and no return to normality occurs in only 8% of cases, but in 35%, the course is characterized by an impairment increasing with each further episode and no return to normality, s It is not yet clear whether relapse prodromes resemble the initial prodromes preceding the first episode of psychos i s . 6 To answer this question would require a longitudinal prospective study in a high-risk population. The present report will mainly refer to prodromal states prior to relapse. PRODROMAL STATES AND THE VSC MODEL The VSC model is the most influential heuristic concept in understanding the development of schizophrenic relapse and illness course. 7-9 Based on this model, Zubin et alJ ° formulated the following hypotheses on the development of relapse:
ComprehensivePsychiatry,Vol. 41, No. 2, Suppl. 1 (March/April), 2000: pp 76-85
PRODROMAL STATES IN SCHIZOPHRENIA
• Relapse is an indigenous characteristic of a
subtype of schizophrenia which occurs in some patients regardless of treatment, i.e., they possess a special vulnerability which is not present in non-relapsers. • Relapse occurs only as a result of a life-event stressor. • Relapse occurs when the individual's coping ability (with or without the assistance of therapeutic intervention) no longer serves to screen out the impinging stressors, which formerly could be contained. • Some combination of the above mechanisms may interact to increase the likelihood of relapse. Hence, the course of illness seems to depend on the interaction of vulnerability factors, stressors, and protectors. Increases in either vulnerability and/or stressors or decreases in protective factors are viewed as possible sources to move the vulnerable system from a stable state of remission via intermediate and prodromal states 8 to a destabilized state of psychotic exacerbation. According to Nuechterlein, 8 "intermediate states" are characterized by the following deviant psychophysiological processes: • Processing capacity overload • Tonic autonomic hyperarousal • Deficient processing of social stimuli. Prodromal states occur when the individual vulnerability threshold is crossed by excessive internal or external stressors and, at the same time, adaptive strategies, e.g., coping or support, are not available. 4 The outcome of this complex interaction depends on the following: • Extent and duration of the stressor • Individual's perception of that stressor • Individual's ability to control and regulate dysphoric affects • Individual's coping skills • Presence of social supports • Promptness and effectiveness of psychiatric intervention. If "prodromal-type symptoms" are not effectively counteracted, the phenotypically indistinguishable "prodromal phase" may occur and develop into a full-blown relapse. Hence, prodromal symptoms may indicate an imbalance of the VSC system; identification of the underlying processes could provide better understanding of the developing psychopathology and psychophysiology of schizophrenia ll:2 and also could be of predictive value to
77
initiate therapeutic actions. Research is needed to clarify the distinction between the appearance of sporadic prodromal-type symptoms and the onset of the prodromal phase of relapse in schizophrenia. In this regard, biochemical, psychophysiological, or other markers of the prodromal phase of relapse need to be established. 4 PRODROMAL SYMPTOMS
Definitions and Descriptions The concept of prodromal symptoms in general is usually retrospective: prodromes will be identified as such only after the development of definite symptoms and signs of first manifestation or relapse. Current definitions of prodromal symptoms are given in Table 1. DSM-III-R 13 contained a description of prodromal features focusing mainly on observable behavioral changes. The list of prodromal symptoms is as follows: 1. Marked social isolation or withdrawal 2. Impairment in role functioning 3. Markedly peculiar behavior 4. Impairment in personal hygiene and grooming 5. Blunted or inappropriate affect 6. Digressive, vague, overelaborate, or circumstantial speech, or poverty of speech, or poverty of content of speech 7. Odd beliefs or magical thinking 8. Unusual perceptual experiences 9. Marked lack of initiative, interest, or energy. Because of uncertainty about their nature, specificity, and reliability of measurement, within current diagnostic systems, prodromal features of schizophrenia are not particularly mentioned. According Table 1. Definitions of Prodromal Symptoms Study Keith and Matthews (1991) 46
Definition
A heterogeneous group of behaviors temporally related to the onset of psychosis Loebel et al. (1992) 47 The time interval from onset of unusual behavioral symptoms to onset of psychotic symptoms Beiser et al. (1993) 48 The period from the first noticeable symptoms to first prominent psychotic symptoms Yung and McGorry A period of prepsychotic distur(1996) 6 bance, representing a deviation from a person's previous experience and behavior
78
to DSM-IV, 14 "prodromal symptoms are often present prior to the active phase, and residual symptoms may follow it. Some prodromal and residual symptoms are relatively mild or subthreshold forms of the positive symptoms . . . . [I]n addition to these positive-like symptoms, negative symptoms are particularly common in the prodromal and residual phases and can often be quite severe" (p. 278). The ICD-1015 acknowledges prodromes as part of the schizophrenic syndrome and describes them in a manner that they may precede the onset. However, prodromal symptoms are not explicitly listed in ICD-10 diagnostic criteria. According to clinical observations, schizophrenic decompensation develops in stages gradually o v e r t i m e . 16A7 In marker terminology, relapse prodromes would specify as episode markers, 18i.e., either psychopathological or biological symptoms and/or signs indexing the very beginning of an acute exacerbation of the illness and covarying with its course. To identify the prodromal state as a subthreshold psychopathological syndrome, it is necessary to differentiate between general/unspecific, more specific/prepsychotic prodromal, and elaborated psychotic symptoms. There is debate as to whether it is methodologically possible and clinically useful to differentiate between these kinds of symptoms. 6,19 As yet, it is not definitely clear whether nonspecific/general symptoms always occur prior to more specific symptoms or whether as Malla and Norman 19 suggested--unspecific symptoms, like anxiety, may actually be reactions to early but hidden psychotic symptoms. Therefore, it would be important to assess specific and unspecific symptoms. It may be of practical value to detect more specific symptoms indicative of the onset of a psychotic episode, because generalized symptoms may depend on or are influenced by several factors other than impending exacerbation. 4
Measurement For the assessment of prodromal symptoms, a number of instruments have been developed. Some instruments, such as the Frankfurt Complaint Questionnaire, 2° e.g., were not specifically developed for monitoring prodromal symptoms, whereas others, like the Instrument for the Retrospective Assessment of Onset and Early Course of Schizophrenia, 21 were specifically designed to record the
GAEBEL ET AL
beginning and initial prodromes of schizophrenia. On the other hand, the Early Signs Scale 22 or the Early Signs Questionnaire (ESQ) 23 were developed for the assessment of relapse prodromes on the basis of systematic studies in large samples of patients and family informants. However, these retrospective studies and their instruments suffer from methodological difficulties like "effort after meaning" or the "degree of sealing over. ''6
Symptom Prevalence and Profile To elucidate the relationship of prodromal symptoms and the onset of a psychotic relapse, data from a German multicenter study on intermittent versus maintenance neuroleptic long-term treatment in schizophrenia (ANI Study l) were reanalyzed with respect to the prevalence and profile, nature, time course, and predictive value of prodromal symptoms in schizophrenic relapse (see also Gaebel et
al.2). The German Neuroleptic Treatment Study (ANI) group was established between 1980 and 1983 and developed the project design of the present study concerned with the early-intervention treatment approach. The ANI Study lasted from 1983 to 1989 with an observation phase of 2 years. The main aim of the study was to demonstrate whether this approach was feasible and effective using a broad spectrum of target measures in a large patient sample. Contrary to other studies on intermittent treatment, a specially designed control strategy was included to evaluate the relapse-predictive validity of prodromal symptoms. Three randomly assigned open neuroleptic treatments (with conventional neuroleptics) were compared in 364 schizophrenic outpatients (ICD-9, 24 and Research Diagnostic Criteria 25) after informed consent: standard prophylactic maintenance medication, and 2 types of intermittent treatment (early intervention and neuroleptic crisis intervention). The frequency of contacts was initially a minimum of once in 2 weeks (if necessary, even more frequently), but could be later reduced to once in 4 weeks in case of stable clinical conditions. Treatment decisions within a particular strategy were based on clinical assessment according to defined psychopathological and psychosocial criteria. The Brief Psychiatric Rating Scale (BPRS) was used to measure changes in psychopathology, the Global Assessment Scale (GAS) was used to measure changes in psychosocial adjustment related to symptomatology, and the CGI was used to
PRODROMAL STATES IN SCHIZOPHRENIA
79
Table 2. Prevalence of General Prodromes (%) All Patients B e f o r e Therapy (n - 1 5 8 )
Prodrome Depression Trouble concentrating Trouble sleeping Tense and nervous Restlessness Loss of interest
Maintenance Treatment (n = 70)
Intermittent Treatment (n = 88)
Differences Between Treatment Strategies(P)*
30 34 19 18 19 24
31 28 31 27 24 18
NS .0001 .0001 .0001 .0001 .0001
49 75 83 71 79 56
*Chi-square test.
measure changes in the degree of illness severity. Relapse, in particular, was clinically defined as a psychotic deterioration of maximum intensity usually demanding hospitalization, but in addition by certain minimum change scores on the indicated instruments. Although relapse rates were significantly lower under early intervention (49%) than under crisis intervention (63%), those under maintenance treatment were by far the lowest (23%). Dropout and rehospitalization rates under both intermittent treatment strategies were also significantly less favorable than under maintenance treatment, whereas psychopathology, social adjustment, subjective wellbeing, and side effects were not significantly different between treatment strategies. Cumulative neuroleptic dosage was significantly lower under intermittent treatment, even when inpatient treatment in case of rehospitalization was considered. The prodromal scale was adapted from the Early Symptom Questionnaire (ESQ), 23 and the items are listed in Tables 3 to 5. Prodromal symptoms were classified into 6 general (unspecific) prodromes which had to be rated at each contact, and an additional 3 optional prodromes which could be selected from a list of 16 symptoms consisting of unspecific and specific prodromes as well as from individual items. (It may be seen as a methodological limitation that only 3 additional prodromal
symptoms were selected, rendering the description of prodromal symptomatology incomplete.) Besides the presence of prodromes, their severity could be recorded by a scale ranging from 0 = not existing, over 1 = slight, 2 = moderate, to 3 = severe. Thus, a score for severity could be computed for each patient for each assessment (general prodromes: unweighted sum of 6 items, min = 0, max = 18). The sample consisted of 158 schizophrenic patients who completed the observation phase of the study. The mean age (mean ___SD) of the 67 male and 91 female patients was 35 --- 9.1 years. The prevalence rates of prodromes for all patients at the beginning of the study and during the 2-year treatment phase are shown in Tables 2, 3, and 4. Remarkably, the frequencies of general prodromes assessed at the beginning of the study-besides depression--were significantly higher than throughout the study phase (Table 2). These figures are in the same range as the frequencies of general symptoms reported by Herz and Melville 23 from their retrospective assessments. The same trend holds true for the additional unspecific (Table 4) and specific (Table 3) prodromes, the low prevalence rates being partly explained by the method of recording the additional prodromes (already described). The ratings at the beginning of the study
Table 3. Prevalence of Additional Specific Prodromes (%) Prodrome Feeling of being controlled Feeling of being laughed at or being watched Hallucinations (visual, acoustic) Fear of going crazy Acoustic sensitivity More religious thinking Incoherence Bad dreams *Chi-square test.
All Patients Before Maintenance Therapy (n = 158) Treatment(n ~ 70) 6 11 6 4 4 5 4 2
1,9 1.4 1.8 1.2 0.4 0.9 0.3 0.1
Intermittent Treatment(n = 88)
Differences Between TreatmentStrategies (P)*
3.1 3.2 1.8 1.0 1.8 1,1 1.2 0.6
NS .0001 NS NS .0001 NS .0001 .0001
80
GAEBEL ET AL
Table 4. Prevalence of Additional Unspecific Prodromes (%) Prodrome Social withdrawal Loss of happiness Loss of appetite Loss of interest Forgetfulness Feeling worthless Feeling bad for no reason Loss of hygiene
All Patients B e f o r e Therapy (n = 1 5 8 )
Maintenance Treatment (n = 70)
Intermittent Treatment (n = 88)
DifferencesBetween Treatment Strategies (P)*
12 2 7 2 2 2 2
3.2 0.8 1.0 1.6 0.4 0.3 0.4
3.2 0.5 1.0 0.5 0.6 0.6 0.4
NS NS NS .0001 NS NS NS
1
0.5
0.4
NS
*Chi-square test.
were retrospective, asking patients and their families how their previous episode had begun. Obviously, the prevalence of prodromes assessed retrospectively-after a relapse has occurred--yields higher rates compared with prospective assessment, possibly due to the methodological influences described before. Remarkably, the prevalence of general as well as additional specific and unspecific prodromes seems to depend on the treatment strategy. The prevalence of all general prodromes is significantly different between treatment strategies, except for depression. Whereas trouble concentrating and loss of interest prevail under maintenance treatment, trouble sleeping, being tense and nervous, and restlessness prevail under intermittent treatment. Both additional unspecific (Table 4) and specific (Table 3) prodromes occur more frequently under intermittent treatment---especially feelings of being controlled, feelings of being laughed at or being watched, acoustic sensitivity, incoherence, and bad dreams---except loss of interest, for which it is the reverse. This consistently specific pattern of prodromes in the different treatment strategies may be interpreted as follows. Under intermittent treatment, still-unspecific prepsychotic (trouble sleeping, being tense and nervous, and restlessness) as well as already specific prepsychotic symptoms seem to prevail--indicating a higher proportion of time spent in prodromal states according to the significantly higher relapse rate under this treatment. Under maintenance treatment, on the contrary, prodromes are less prevalent in concordance with the lower relapse rate. However, trouble concentrating and loss of interest, both showing a higher prevalence under this treatment strategy, may be seen as neuroleptic side effects. This interpretation is corroborated by the fact that under maintenance treatment patients were subjected to
significantly higher cumulative neuroleptic dosages as compared with intermittent treatment.
Nature of Prodromal Symptoms To further elucidate the nature of prodromal states, the relationship between general prodromal symptoms (sum score) and psychopathology, neuroleptic side effects, and social functioning was analyzed (Fig 1). All correlations (Pearson's product-moment correlations) were computed for the same time of assessment throughout the study phase. Prodromes are a category of symptoms on their own, but they share variance with the different areas, ranging from 4% (Extrapyramidal Symptom Scale; EPS) to 30% (BPRS subscore schizophrenia). Interestingly, side effects partly overlap with prodromes (Dosage Record and Treatment Emergent Symptom Scale; DOTES 19%), better social adjustment is associated with less pronounced prodromes (GAS 23%), and of the 3 psychopathological syndromes of the BPRS besides schizophrenic symptomatology, anxiety-depression (26%) shows greater overlap than anergia (6%). Marder et
~
~
,a~ilnsTEa Al..... l nificS~a resig nt
Fig 1. Pearson's product correlation coefficients between score of general prodromes and other domains.
PRODROMAL STATES IN SCHIZOPHRENIA
81
2, ...............................................................................................................
~
1,
E
!1 s
I 0,,"
1 2 3 4 5 6 7 8 9 101112131415161718192021222324
Month after beginning of the study Fig 2.
l i m e course of the mean general prodromal score.
al. 26 have also reported on the (limited) prodromal significance of the BPRS anxiety-depression cluster. Altogether, these findings indicate that treatment side effects, dysphoric mood (related to side effects?), and social dysfunction seem to be associated with prodromal states--the direction of this association, however, is still to be clarified. Prodromal symptoms are not independent of the neuroleptic treatment strategy and correlate significantly with psychopharmacological side effects without being completely explained by them--findings which are in line with the results of Jolley et al. 27 concerning the superiority of continuous neuroleptic medication in preventing both psychotic and dysphoric morbidity in schizophrenia. Illness Course and Predictive Validity The course of the mean prodromal score during the 2 years of observation for all patients is shown in Fig 2. It is an irregular course, with a slight increase within the second half of the study. Taking into account the possible maximal value of 18 points, the average is on a very low level. It must be taken into account that the mean prodromal score refers to the whole sample, not differentiating
between the occurrence of relapse, time of relapse, or treatment strategy. If one wishes to examine the power and time window for prodromes in predicting the clinical course, correlations between prodromes and psychotic syndromes should be calculated for varying time intervals throughout the illness course. As already shown, correlations between general prodromes and the BPRS schizophrenia subscore at the same time of assessment amounted to an r value of .55, explaining 30% of the variance, a moderate level of "predictive" power. It can be expected that with successively increasing time intervals, correlations between prodromes and symptoms will decrease. To elucidate the influence of the time interval, we combined a fixed measurement of symptoms at different points of the course with time-lagged measurements of prodromes. The considered time window had a length of 4 weeks and was 3 times backward-shifted. Results of these analyses are shown in Table 5 and Fig 3. In concordance with expectations, correlations between general prodromes and the 3 psychopathological syndromes decrease with increasing time intervals. Associations between prodromes and the BPRS anxiety-depression factors are strongest for all BPRS subscores. However, although systematic measurements within the 4-week period are missing, it may be expected from Fig 3 that more powerful predictions could be made within this 4-week time window. In accordance with the literature, the main prodromal changes occur within 4 weeks prior to a relapse, =2,23,28probably maximizing correlations between psychopathology and prodromal symptoms during this phase. This analysis did not yet take into account whether the simultaneous correlations between prodromes and psychopathology as shown in Table 5 and Fig 1 remain stable or differ between 3 main phases of the illness course: baseline (remitted) phase, prodromal phase, and relapse phase. For further analysis, these phases were defined as follows: baseline phase,
Table 5. Correlations Between Score of General Prodromes and BPRS Syndromes for Different Intervals of l i m e Score of Prodromes 2-3 Months Before
1-2 Months Before
0-4 Weeks Before
r
No.
r
No.
r
No.
r
No.
Schizophrenia
.17
3,094
.24
3,168
.24
2,568
.55
4,256
Anxiety/depression
.28
3,095
.32
3,169
.29
2,569
.51
4,257
Anergia
.16
3,095
.17
3,169
.17
2,569
.25
4,257
BPRS Subscore
NOTE. All correlations are significant (Pearson's product correlation coefficient).
At the Same "rime
82
GAEBEL ET A L
0.6 -
0,5
- B P R S - S u b s c o r e Anxiety/Depression B P R S - S u b s c o r e Schizophrenia ~_ B PRS-Subsc___ore Anergie_ _ _
I I J
0,4
0,3
-*ill
0,1
0
2 - 3 months before
1 - 2 months before
0 - 4 weeks before
first 6 months of the study, excluding relapsing patients during the first year; prodromal phase, 3 months prior to a relapse; and relapse phase, according to predefined relapse criteria.l This differentiation allows for answering the question of the stability of simultaneous correlations according to Table 5 for different phases of the illness course. As follows from Table 6, the correlations during the baseline and prodromal phase are mainly preserved, whereas those during the relapse phase decrease dramatically. It should be mentioned that the differences between phases do not depend on the different number of observations. During the baseline, we have about 6 observations per patient, during the prodromal phase, we have about 3 observations per patient, and during relapse, we have only 1 observation per patient. By analyzing only 1 observation per patient of each phase, the correlations do not change. It may be assumed that prodromal symptoms are associates of psychopathology up to a certain severity and, as such, are predictors of relapse, but in the case of relapse, they either may not linearly increase with symptomatology or may be indistinguishable from very pronounced psychotic symptoms. But it must also be taken into consideration that the correlations were computed for all relapsing patients irrespective of the existence of a
at the same time
Fig 3. Correlations between score of general prodromes and BPRS syndromes for different intervals of time (Pearson's product correlation coefficient).
prodromal phase. It may thus be possible that prodromes as a "personalized relapse signature ''29 would have correlated more strongly with psychopathology if cases without prodromal states were excluded.
Relationship to Relapse Not only may prodromal states occur without a following exacerbation, but relapses may also develop without a preceding prodromal state. Marder et al., 3° in patients under maintenance treatment with depot neuroleptics, observed a prodromal state preceding 37% of relapses, but in 52%, a prodromal phase was not followed by a psychotic exacerbation. The prevalence of relapses preceded by nonpsychotic prodromal signs reported by Jolley et al. 27 was 53%. Within our sample, 41% of all patients failed to show prodromal symptoms during the 3 months before a relapse occurred. The relapse predictive validity of prodromal symptoms has been assessed in a number of studies, including o u r o w n . 19,28-32 A sensitivity of 8% to 81% and a specificity of 70% to 93% has been f o u n d , 33 with our own findings being at the lower end of the range: especially in the nonintervention group (crisis intervention), sensitivity was 10% and specificity 93%. With a corresponding
Table 6. Correlations Between Score of General Prodromes and BPRS Syndromes During Different Phases of Illness Course Baseline BPRS Subscore
Prodromal Phase
Relapse
r
No.
P
r
No.
P
•
No.
P
Schizophrenia
.53
722
.0001
.44
227
.0001
.23
74
.04
Anxiety/depression
.56
722
.0001
.56
227
.0001
.34
74
.002
Anergia
.29
722
.0001
.26
227
.0001
.04
74
.7
NOTE. Pearson's product correlation coefficients are shown.
PRODROMAL STATES IN SCHIZOPHRENIA
positive predictive value of 43%, it becomes clear that relapse prediction from prodromal symptoms is no better than by chance, whereas a negative predictive value of 67% demonstrates that indeed no prodromal symptoms are more often followed by nonrelapse. However, in accordance with this reasoning, it could be shown that the "hit" rate of correctly predicted relapses depended on the time interval between prodrome and relapse: predictions, on average, 2 weeks before a relapse were successful, whereas those more than 3 weeks before were not. Consequently, the monitoring of prodromes should occur at least every 2 weeks.
Early Intervention Strategies For a long time, research has focused on the development of predictors of relapse in individual patients to restrict treatment to only those patients who obviously need it. Since demographic, clinical, and biological variables are of only limited usefulness in this respect, 34 an alternative approach has been adopted. On the basis of early reports on unspecific prodromal symptoms preceding a relapse, 23 the rationale of early-intervention, timelimited, targeted neuroleptic treatment was developed. Contrary to earlier positive findings in selected patients, 35-38 however, all recently completed controlled 2-year studies on early-intervention treatment have not confirmed this strategy to be as effective as maintenance treatment in preventing relapse. 3942 Even those studies applying early neuroleptic intervention within an enriched psychosocial program 39-42 did not consistently lead to better outcome compared with those that did not. 4° Our own study 1 similarly led to disappointing results, although the early-intervention strategy based on prodromal symptoms was more favorable than the crisis intervention. Moreover, as a recent reanalysis demonstrates, first-episode patients seem to profit most from early intervention but less from maintenance treatment as compared with multiple-episode patients. These findings need replication. CONCLUSIONS
The rationale of intermittent treatment is based on the assumption that relapse is an episodic phenomenon in stabilized schizophrenics, that prodromal symptoms are valid predictors of relapse, and that impending relapse can be prevented by early neuroleptic intervention. Concerning the possible reasons for the failure to correctly predict
83
relapse particularly under crisis intervention2--a control strategy specially chosen to empirically test the predictive validity of prodromal s y m p t o m s - methodological problems may have obscured the correct and timely determination of the onset of psychosis. For instance, the wrong symptoms may have been chosen as potential predictors, i.e., the symptoms collected by Herz and Melville 23 by expost-information may have simply been subject to a "hindsight bias" of the patients and their families. In fact, the studies by Marder et al., 26 JohnstonCronk et al., 43 and Marder et al. 3° also failed to demonstrate their predictive validity. Symptoms assessed in other studies either have not been made explicit or are doubtful regarding their prodromal status. We, for instance, kept strictly to nonspecific, i.e., nonpsychotic, symptoms, which might explain their predictive failure. Because certain prodromal symptoms seem nosologically unspecific, 44 their relationship to schizophrenic relapse may not be as consistent as required for reliable prediction. In conclusion, taking together the presently available results from all controlled 2-year intermittent treatment studies, including our own, the application of this treatment of this treatment strategy cannot be generally recommended. A greater burden on the patients and their families, 41 greater demands on treatment facilities, restricted feasibility, as well as overall poorer results contribute to this conclusion. Even though all target measures besides relapse do not show any significant differences, we still consider relapse a serious event in patients' lives that should be prevented. From the perspective of maintenance treatment, which was correctly hypothesized to be the superior treatment in this respect, there seems to be no greater harm to the patients compared with intermittent treatment--at least over the observed p e r i o d - concerning social adjustment, subjective wellbeing, or side effects, despite higher cumulative dosages. On the other hand, from the perspective of early intervention, there seems to be no particular benefit. According to beneficial experiences in individual cases, however, this approach is still the only possible way to identify patients who do not need continuous treatment. Since treatment failure is not necessarily followed by rehospitalization, early-intervention treatment should be encouraged in selected cases where patients themselves will accept the risk for specified individual reasons. In
84
GAEBEL ET AL
accordance with clinical guidelines for selection of these patients, 45 stable remission seems to be the most important prerequisite; additionally, patient cooperativeness, integrative coping behavior, supportive environment, and continuously available outpatient services are facilitating conditions for an early-intervention trial. Prodromal s y m p t o m s hence could be a clue to better understand the clinical d e v e l o p m e n t and pathophysiology of illness manifestation and relapse. W h e t h e r they reflect vulnerability, stress reactivity, coping effort, or all of these c o m b i n e d is still u n k n o w n . Remarkably, a sizable n u m b e r of patients do not present with prodromes before r e l a p s e - - a finding which m u s t be a c c o m m o d a t e d b y any theory linking them to the VSC m o d e l and to relapse. Their relationship with clinical psychopathology is obvious from our data however, correlations m a y be clinically m e a n i n g f u l to use for prediction only within a narrower time w i n d o w of 2 weeks. O n the other hand, the closer to relapse prodromes are assessed, the lower the correlations with psychopathology will b e - - a paradox which
m a y either be methodologically explained or reflect a n o n l i n e a r relationship b e t w e e n the 2 domains. The different prevalence rates of prodromes under m a i n t e n a n c e a n d intermittent treatment strategies m a y be understood as an indirect argument for their relapse connotation, although their direct predictive value seems q u e s t i o n a b l e - - a t least u n d e r the methodological constraints of the studies. Moderate correlations with neuroleptic side effects, on the other hand, point to the fact that prodromes have different sources of origin which should be considered from a conceptual and methodological perspective. In summary, future research should clarify the nature o f prodromal symptoms, especially with respect to the V S C model, their unbiased recognition, their relationship with relapse, and the question of the stability of initial and relapse prodromes. W h e t h e r first-episode patients, in particular, profit from a trial with prodrome-guided early-intervention strategies should be the focus of u p c o m i n g research.
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