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Psychosomatic Medicine 66:538-547 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Treatment of Somatoform Disorders With St. John’s Wort: A Randomized, Double-Blind and Placebo-Controlled Trial

Thomas Müller, MD, Marcus Mannel, MD, Harald Murck, MD and Volker W. Rahlfs, Cstat (RSS)

From the Department of Neurology, Ruhr-University Bochum, Germany (T.M.); Ad libitum Medical Services, Berlin, Germany (M.M.); Lichtwer Pharma GmbH, Berlin, Germany (H.M.); and idv – Datenanalyse und Versuchsplanung, Gauting, Germany (V.W.R).

Address correspondence and reprint requests to Dr. Thomas Müller, Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University of Bochum, Gudrunstr. 56, D-44791 Bochum, Germany. E-mail: thomas.mueller{at}ruhr-uni-bochum.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: To investigate efficacy and safety of St. John’s wort (SJW) LI 160 in somatoform disorders.

METHODS: In a prospective, randomized, placebo-controlled, and double-blind parallel group study, 184 outpatients with somatization disorder (ICD-10 F45.0), undifferentiated somatoform disorder (F45.1), and somatoform autonomic dysfunction (F45.3), but not major depression, received either 300 mg of SJW extract LI 160 twice daily or matching placebo for 6 weeks. Six outcome measures were evaluated as a combined measure by means of the Wei Lachin test: Somatoform Disorders Screening Instrument – 7 days (SOMS-7), somatic subscore of the HAMA, somatic subscore of the SCL-90-R, subscores "improvement" and "efficacy" of the CGI, and the global judgment of efficacy by the patient.

RESULTS: In the intention to treat population (N=173), for each of the six primary efficacy measures as well as for the combined test, statistically significant medium to large-sized superiority of SJW treatment over placebo was demonstrated (p <.0001). Of the SJW patients, 45.4% were classified as responders compared with 20.9% with placebo (p = .0006). Tolerability of SJW treatment was equivalent to placebo.

CONCLUSIONS: Administration of 600 mg of SJW extract LI 160 daily is effective and safe in the treatment of somatoform disorders, thereby confirming results from a previous study.

Key Words: somatoform disorders, • depression, • hypericum, • St. John’s wort, • LI 160, • clinical trial.

Abbreviations: SJW = St. John’s wort;; SSRI = selective serotonin reuptake inhibitor;; CBT = cognitive behavioral therapy;; GCP = good clinical practice;; GMP = good manufacturing practice;; IDCL = international diagnostic checklists;; ICD = international classification of diseases;; DSM = Diagnostic and Statistical Manual for Mental Disorders;; SOMS = Somatoform Disorders Screening Instrument;; HAMA-SOM = Hamilton Anxiety Scale, somatic subscore;; HAMA-PSY = Hamilton Anxiety Scale, psychic subscore;; HAMD = Hamilton Depression Rating Scale;; SAD = somatoform autonomic dysfunction;; SD = somatization disorder;; SCL-90-R-SOM = Symptom Check List 90 Revised, somatization subscore;; CGI = clinical global impression;; ITT = intention to treat (population/analysis);; PP = treated per protocol (population/analysis);; LVCF = last value carried forward;; MW = Mann-Whitney estimator;; CI = confidence interval.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
According to the current concepts of DSM-IV (1) and ICD-10 (2), somatoform disorders are mainly characterized by chronic multiple physical symptoms that cannot be explained in terms of underlying organic pathology. Another characteristic of patients with somatoform disorders is their persistent conviction of being physically ill despite numerous negative medical examinations and tests, expert opinion, and even recurrent hospitalizations. Patients with multiple somatic complaints not only confront medical professionals with serious management problems, but they also frequently suffer from severe functional impairments that may outweigh those of patients with other severe mental illnesses or chronic organic diseases (3,4). Patients with somatization disorder feel ill and spend an average of 7 days per month in bed (4).

Epidemiological data for specific somatoform disorders are rare. The prevalence rate for somatization disorder has been estimated to be about 0.5% (5,6). However, prevalences of clinically relevant somatization syndromes that do not fully meet the restrictive diagnostic criteria for somatization disorder reveal the full scale of the problem much better. An attenuated form of somatization with a 2-year history that is currently characterized by three or more worrisome symptoms was observed in 8.2% of primary care patients (7). Escobar et al. reported rates between 4.4% and 20% for their abridged somatic symptom index (SSI), which they developed from the Diagnostic Interview Schedule (6). Rief et al. found base rates for single somatoform symptoms of up to 30% (8).

Although identified as frequent and severe illnesses with enormous socioeconomic impact, somatoform disorders are infrequently seen by many psychiatrists, and they are probably the most common psychiatric disorder to present in nonpsychiatric settings (9). Owing to the nature of the disease, outpatients are seeking help with primary care physicians and somatic specialists, not psychiatrists.

Treatment of somatization syndromes is primarily based on coping and management strategies. A recent systematic review of 31 controlled clinical trials found cognitive behavioral therapy (CBT) to be effective in a total of 1689 patients suffering from various somatoform syndromes (10).

Only few data exist on the efficacy of pharmacotherapy in somatoform disorders. Volz et al. concluded that most drug trials do not satisfy diagnostic and other methodological requirements (11). A small number of mainly open-label trials assessed mostly SSRIs in somatoform pain disorders (12–14), hypochondriasis (15,16), body dysmorphic disorder (17,18,19), and other somatoform disorders (20,21). In the only large placebo-controlled trial, the tricyclic compound opipramol was found to be effective in somatoform disorders (22). SSRIs and other antidepressants exhibited some positive effects in other somatoform spectrum disorders, eg, premenstrual syndrome, fibromyalgia, or chronic fatigue syndrome (23–26).

Significant evidence suggests that St. John’s wort (SJW) is an effective treatment for mild to moderate depressive disorders (27,28), and from some depression trials noticeable improvements of somatic symptoms have been reported (29,30,31,32). Data from pilot studies in chronic fatigue (33), premenstrual syndrome (34), and climacteric syndrome (35) further point to a significant effect of SJW on multiple somatic complaints. In a recent trial, 600 mg daily of the SJW extract LI 160 was significantly better than placebo, as measured by the decrease on the somatic subscore of the Hamilton Anxiety Scale (HAMA-SOM). This was independent of the course of comorbid mild depressive symptomatology (36).

As the HAMA-SOM is not an instrument validated for the assessment of somatoform disorders, a novel rating scale - the Somatoform Disorders Screening Instrument (SOMS) - was introduced to assess treatment effects in a more specific way (37). Objectives of this randomized, placebo-controlled and double-blind trial, were to verify the efficacy of SJW treatment in somatoform disorders and to compare outcomes on the SOMS with those on other rating scales.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Patients
Female and male outpatients aged 18 to 65 years with unexplained multiple somatic symptoms were enrolled for screening procedures in participating centers. Patients meeting ICD-10 criteria for somatization disorder (F 45.0), undifferentiated somatoform disorder (F 45.1), and somatoform autonomic dysfunction (F 45.3) were to be included in the trial. The baseline somatic subscore of the HAMA-SOM had to be at least 12, and the psychic subscore (HAMA-PSY) had to be at least 5 points less than the HAMA-SOM, analogous to the two recent drug trials in somatoform disorders (22,36). The Hamilton Depression Scale (HAMD) score at baseline was not allowed to exceed 12 points, in order to exclude significant comorbid depression.

Investigators used the semi-structured International Diagnostic Checklists (IDCL) for diagnosis, an instrument co-developed and recommended by the WHO for use in research and everyday patient examinations (38,39). Compared with other structured interviews, the IDCL allows for more flexibility and provides the clinician with a more comprehensive overview of how individual criteria are combined in a specific diagnosis. This offers some advantages in clinical trials in a primary care setting like ours. It has not been validated specifically for somatoform disorders, retest reliability figures for "major depression," "anxiety disorders," and "affective disorders" range from rtt=0.73 to 0.83 (40). Thus, comparable validity may be expected for the application to somatoform disorders.

Investigators were trained by an expert in a standardized fashion on the use of diagnostic procedures and rating scales, in a 1-day session before the start of the study. More than half of the investigators had already participated in a previous somatoform disorders trial and relating training procedures.

To further verify diagnoses and to assess treatment outcome, the SOMS was used. The SOMS has been developed and validated by Rief et al. to diagnose and monitor somatoform disorders along the ICD-10 and DSM-IV criteria and to better distinguish them from anxiety disorders (41,42).

Two versions of the SOMS are available. The SOMS-2 asks for the presence of 53 physical complaints lacking an organic disease during the previous 2 years and verifies further classification criteria with another 15 questions to be answered by the patient. The questionnaire includes all 33 physical complaints of the DSM-IV somatization disorder symptom list, the symptoms of ICD-10 somatization disorder, and the ICD-10 somatoform autonomic dysfunction symptom list. Therefore the SOMS-2 is suitable to screen for the presence of somatoform disorders. The SOMS-7 asks the patient to rate the intensity of those complaints (0 = not present; 1 = mild; 2 = moderate; 3 = severe; 4=very severe) during the last 7 days and has demonstrated to discriminate patients with different severity and to be sensitive to assess change (37). In previous studies with clinical samples, the number of somatoform symptoms according to the SOMS was correlated with the number of somatoform symptoms according to a standardized psychiatric interview. Adding the number of positively answered symptoms allows computation of the "somatization index." The number of somatization symptoms correlated r = 0.75 between self-ratings and interview, confirming the high validity of the SOMS. The 72-hour retest reliability was found to be rtt = 0.85. In an investigation of a high-risk group of patients, somatoform disorder diagnosis according to the questionnaire was compared with interview data. Scores for sensitivity were in the range between 86% (SAD-ICD-10) and 100% (SD-DSM-IIIR), and scores for specificity were between 43% (SAD-ICD-10) and 85% (SD-DSM-IV) (42). These data imply that the SOMS provides acceptable estimates for somatoform disorders.

In our study, only patients with a baseline SOMS-2 score ≥ 4 (male patients) and ≥ 6 (female patients) were included. This criterion has been introduced by Escobar et al. to identify somatization syndromes of clinical relevance beyond DSM diagnosis (6). Further, baseline SOMS-7 score had to be 12 to 30, representing a sample with mild to moderate symptom severity.

Patients exhibiting a decrease in SOMS-7 score > 6 during the placebo run-in phase ("placebo responders") were not to be included in the trial.

Major exclusion criteria were: current diagnoses of major depression, drug and alcohol abuse, epilepsy, organic mental disorder, and any other serious unstable acute or chronic medical condition; current or anamnestic diagnosis of schizophrenia or schizo-affective disorder; use of psychotropic drugs 4 weeks before and during the study; concurrent psychotherapy; increased suicidal risk; need for concomitant treatment with phenprocoumon and/or cyclosporin; and the standardized GCP criteria for study participation.

From August 1999 to February 2000, 11 general practitioners, 7 psychiatrists, and 2 internists enrolled a total of 184 individuals to undergo screening procedures; 175 were randomized, 173 subjects entered ITT analysis, and 164 patients lacking major protocol violations were the basis of the PP population (Figure 1).



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  		Figure 1. Flow diagram of subject progress through the trial and allocation to analysis populations. Primary efficacy analysis was performed with the ITT population, comprising all patients randomized with at least baseline efficacy ratings. A supportive efficacy analysis was carried out with the PP population, consisting of all patients lacking major protocol violations and with a compliance rate ≥80%.

 
Baseline demographics and clinical characteristics did not differ significantly between groups, except for small-sized differences regarding sex ratio and CGI subscore "severity" (Table 1). A mean number of 14.6 somatoform symptoms during the last 2 years (SOMS) confirmed the multiplicity of complaints in our sample. Mean baseline HAMD scores of 9.2 in both groups reflect low depressive comorbidity at the threshold of clinical significance.


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  		TABLE 1. Baseline Demographics and Clinical Characteristics of Patients (ITT Population)
 
Study Design
The study is a prospective, randomized, double-blind, and placebo-controlled trial, to assess efficacy and safety of a 6-week treatment with SJW extract LI 160 in outpatients suffering from somatoform disorders.

Patients presenting at a study site were informally screened by the investigator by means of an unstructured interview. If eligible, the patient was then invited to participate in the study and underwent formal prebaseline visit screening procedures (week –1). After giving written informed consent, patients entered a single-blind placebo run-in phase. Patients who remained eligible at the baseline visit (week 0) were randomly assigned in a 1:1 ratio to receive either SJW or placebo. Computer-aided randomization and preparation of a coding list (Rancode; Wiedey, Konstanz, Germany) was performed in blocks of six by the independent Quality Assurance Unit of the sponsor. No further stratification was carried out. Blistered study medication and medication containers were labeled sequentially according to the coding list by the manufacturing department of the sponsor and provided to the investigators in blocks of six. All investigators, personnel of contracted partners and of the sponsor who were actively involved in the trial were blinded to group assignment until lock of database at the end of the trial. Success of blinding has not been evaluated systematically in this trial, because experience from previous trials with identical formulations has revealed good results.

After inclusion, patients were seen at weeks 2, 4, and 6. Efficacy ratings, adverse events, concomitant treatments and adherence to treatment (pill counting) were assessed at all visits from week 0 to week 6. Detailed physical examinations, urinary and blood clinical biochemical screening, and vital signs were performed at the screening visit (week –1) and at the end of the study (week 6). Patients also gave global judgments of efficacy and tolerability of treatments at the end of the study (week 6).

The study protocol and patient information materials were approved by federal ethical committees in charge of the participating investigators. The study was performed in full accordance with Good Clinical Practice (GCP) Guidelines and the Declaration of Helsinki and its revisions.

Study Medications
Study medications were provided by Lichtwer Pharma AG (Berlin, Germany).

SJW sugar-coated tablets containing 300 mg of the Hypericum extract LI 160 (drug-extract ratio 4–7:1; extraction solvent 80% methanol in water) or placebo tablets identical in shape, size, taste, and color were administered twice daily.

Overall adherence figures were excellent and comparable between groups with 99.5% (71.4 to 136.7%) of expected drug intake (counted pills) in the SJW group and 99.8% (81.7 to 117.3%) in the placebo group.

Efficacy Measures
Six variables were chosen for primary efficacy analysis: SOMS-7, HAMA-SOM, SCL-90-R-SOM, CGI "improvement," and CGI "efficacy", and the global judgment of efficacy by the patient. The SCL-90-R-SOM used in this study comprised 17 items that were derived from a factor analysis of data from 900 psychosomatic patients (43). SOMS-7, HAMA-SOM, and SCL-90-R-SOM entered analysis as percent changes from baseline to compensate for baseline differences.

Secondary endpoints comprised the HAMA-PSY, CGI "severity of illness," and the proportion of responders, defined as a decrease of ≥ 50% of the SOMS-7 score and a "very much better" or "much better" rating on the CGI "improvement" scale at week 6.

Patients with somatization disorder and with undifferentiated somatoform disorder were combined in one group and were compared with autonomic somatoform dysfunction patients to test for differences in efficacy outcome. This strategy is in line with the ICD-10 approach to diagnostic subgroups of somatoform disorders, where domination of vegetative symptoms separates autonomic somatoform dysfunction on the one side from somatization and undifferentiated somatoform disorders on the other.

Safety Measures
We interviewed patients at each visit for adverse events in an open question fashion to avoid numerous reports of multiple disease-related symptoms. Further, patients rated tolerability in analogy to the CGI "therapeutic risks" (1 = no adverse effects; 2 = impairment not significant; 3 = significant impairment; 4 = risks outweighing therapeutic effect) at the end of the study. Laboratory results, vital signs, and physical examinations provide further information about safety of treatments.

Statistics
Based on an effect size of 0.5, the sample size needed was calculated to be 86 patients per group ({alpha} = 5%; power, 90%).

Primary analysis included all patients randomized with at least one postbaseline efficacy rating (intention-to-treat population, ITT). Missing values were handled conservatively according to the Last Value Carried Forward (LVCF) principle. Primary analysis was applied only to the last value observed (ie, mainly week 6). Because many of the outcome measures were not continuous or might have highly skewed distributions, we chose to use the Wilcoxon Mann-Whitney rank test and related effect size measures to compare the treatments (44). All methods used are in accordance with current European guidelines on statistical principles for clinical trials (45).

Baseline data were analyzed for homogeneity between groups using an univariate confidence interval (CI) approach by means of the Wilcoxon test.

Six primary efficacy variables were tested confirmatorily as an ensemble for the superiority of SJW using the nonparametric directional test (one-sided; {alpha} 2.5%) of the Wei-Lachin procedure. This procedure is a multivariate generalization of the Wilcoxon Mann-Whitney test, which takes account of the correlation among univariate Mann-Whitney tests for each outcome to produce an overall average estimate of benefit and test for treatment differences (46–48). In case of significance of this global test, all primary efficacy variables could be tested individually in an a priori defined sequence without the need for adjustment of type I error for multiple testing. Results of these sequential tests are to be interpreted confirmatorily unless one test fails to significantly prove superiority of SJW (49).

The Mann-Whitney estimator (MW) was used as a measure of relevance of group differences. It is defined as the probability that a randomly selected patient from the test group is more improved than a randomly selected patient from the comparator group. A robust estimator of this probability is implemented by comparing all pairs of patients in which one patient is given the test treatment and the other the comparator treatment. Score 1 is assigned if the test treatment patient responded better; score 0.5, if the two patients are tied, and score 0, if the comparator treatment patient responded better. Then the sum of these scores is divided by the total number of comparisons. Hence, a MW of 0.5 means that patients do equally well under both treatment conditions. MW > 0.5 are evidence of some benefit for the test treatment. The closer MW is to 1, the more reliable is the evidence. Accepted benchmarks for small-, medium-, and large-sized superiority/inferiority are 0.56/0.44, 0.64/0.36, and 0.71/0.29 (50).

We further analyzed the impact of the presence of depressive symptoms on the outcome on the HAMA-SOM by means of a univariate analysis of variance. Presence of depression was defined by a HAMD-17 score > 9 (median baseline score).

Statistical analyses were performed with the software TESTIMATE (v. 5.5) and SmarTest (v. 1.2) of idv Datenanalyse und Versuchsplanung, Gauting, Germany.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Efficacy
For the combined measure as well as for each of the single primary efficacy measures, statistically significant medium to large-sized superiority of SJW treatment over placebo was demonstrated (Table 2). Mean group differences regarding percent changes on SOMS-7, HAMA-SOM, and SCL-90-R-SOM amounted to approximately 20% to 30% in favor of SJW (Figure 2). Correlations of the results of the percent changes of SCL-90-R-SOM, HAMA-SOM, and SOMS-7, and of the global judgment of efficacy by the patient, and CGI-efficacy with the reference CGI-improvement (Pearson r: 0.78, 0.79, 0.83, 0.89, and 0.91 respectively) revealed good agreement of outcome measures.


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  		TABLE 2. Results of Primary Efficacy Analysis (ITT Population; LVCF)
 


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  		Figure 2. Somatoform Disorders Screening Questionnaire - 7 days (SOMS-7), Hamilton Anxiety Scale, somatic subfactor (HAMA-SOM), and Symptom Check List 90 Revised, somatic subfactor (SCL-90-R-SOM) rating scores by week and treatment (ITT population, LVCF). Bars represent means ± standard deviation.

 
At the end of the 6-week treatment period, clearly more SJW patients assessed themselves to be completely improved (44.2%) when compared with placebo patients (24.7%), whereas 44.7% of placebo patients vs. only 17.4% of SJW patients felt unchanged or even worsened (MW, 0.65 [lower bound of one-sided 97.5% CI, 0.57]; p = .0001, Wei Lachin test; Table 2, Figure 3).



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  		Figure 3. Patients’ global judgments of efficacy prove superiority of SJW over placebo (ITT population, LVCF; p = .0001, one-sided Wilcoxon Mann-Whitney test). Bars show groupwise percentages of ratings.

 
Of patients treated with SJW, 51.2% were rated with a SOMS-7 score < 12 (ie, below the threshold for study inclusion) after 6 weeks of treatment compared with 30.2% on placebo.

Furthermore, 45.4% of SJW patients and 20.9% of placebo patients were classified as responders (MW, 0.62 [lower bound of one-sided 97.5% CI, 0.55]; p = .0006, Fisher’s exact test).

Stratified Wilcoxon tests with Cochran-Mantel-Haenszel pooling were carried out as sensitivity analyses to adjust SOMS-7 results (percent changes from baseline) for baseline differences regarding CGI-severity and sex. No significant impact of the observed minor baseline differences could be detected.

There was a trend for better efficacy of SJW in somatoform autonomic dysfunction compared with pooled somatization disorder and undifferentiated somatoform disorder patients (MW combined measure, 0.70 vs. 0.66; Table 3). This trend, however, became obvious only in CGI ratings and the patients’ global judgment of efficacy. No differences between diagnostic subgroups were seen for SOMS-7, HAMA-SOM, and SCL-90-R-SOM ratings.


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  		TABLE 3. Secondary Analysis of Efficacy Outcome Between Diagnostic Subgroups (ITT Population; LVCF)
 
Results in the PP population were nearly identical, thereby corroborating the ITT results.

Regarding HAMA-PSY ratings, mean percent changes from baseline of –44.8% (means of absolute values, 5.5±2.7, baseline, and 3.1±2.7, week 6) in the SJW group and of –8.1% (5.0±2.1 and 4.2±2.7) in the placebo group reflect a comparable efficacy of SJW treatment on comorbid psychic dimensions of anxiety (MW, 0.68 [lower bound of one-sided 97.5% CI, 0.60]; p<.0001, Wilcoxon MW procedure).

There was no significant interaction of drug (SJW vs. placebo) x time x depression (F [164;1] = 2.52; p = .114) regarding the outcome on the HAMA-SOM, which means that the effect of SJW treatment when compared with placebo was not significantly different in patients with lower (≤ 9) vs. those with higher (> 9) HAMD-17 scores at baseline.

Safety
Overall, tolerability and safety of SJW treatment was comparable to that of placebo (Table 4).


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  		TABLE 4. Judgments of Tolerability and Safety of Treatments (ITT Population) and Description of Adverse Events (Safety Population)
 
A total number of 51 adverse events were documented during 6-week treatment; only one was rated by an investigator to be at least possibly causally related to study drug (nightmares, probably related; SJW group). No significant differences between treatments could be elicited with regard to frequencies of specific types of adverse events.

Investigator ratings of tolerability by means of the CGI-therapeutic risks were virtually identical with only one case each of "significant impairment" in both treatment groups, and with 84/87 and 85/88 ratings of "no risks" in the SJW and placebo groups, respectively. Nearly the same figures were obtained by the patients’ tolerability ratings (81 and 82 "very good", 4 and 3 "good", 1 and 0 "moderate" for SJW and placebo, respectively). The lower bounds of one-sided confidence intervals of both ratings indicate non-inferiority in a hypotheses testing sense, thereby statistically demonstrating that tolerability of SJW was "at least as good" as that of placebo.

No significant recordings were reported from analysis of laboratory results, vital signs, and physical examinations.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
We have demonstrated in this trial the efficacy and safety of 600 mg daily of the SJW extract LI 160 in somatoform disorders, thereby confirming results from a previous study (36). Significant and clinically relevant superiority over placebo was not only demonstrated for the combined measure of the six primary efficacy variables, but also for every single measure in the a priori ordered testing sequence. Significant associations of chosen efficacy measures demonstrate a stable effect of the treatment.

Interestingly, a trend for better efficacy of SJW was observed in patients suffering from autonomic somatoform dysfunction. However, this effect was only present in the more simple CGI and a patients’ global efficacy rating, but not in the more sophisticated other rating scales. This observation may reflect an improvement of autonomic somatoform dysfunction symptoms that are not adequately represented by SOMS-7, HAMA-SOM, and SCL-90-R-SOM.

The SOMS is an instrument focusing on patients with multiple unexplained symptoms (somatization disorder, undifferentiated somatoform disorder, and somatoform autonomic dysfunction). This is not only the most frequent subgroup of patients with somatoform disorders (8), but multiplicity of symptoms is also a predictor of persistence and poor outcome (51). As the SOMS was specifically developed for the screening and the assessment of change of these disorders, the present study extends previous findings for SJW and further validates the proof of beneficial effects of SJW for these patients.

Tolerability ratings and adverse events of SJW LI 160 were indistinguishable from corresponding placebo figures. Therefore, both investigators and patients could not have been unblinded by recognizing a specific side effect pattern of SJW LI 160, which further validates the study results.

Adverse event rates appear to be extremely low in our study. Comparable as well as considerably higher figures have been reported from other SJW trials (27). This may be explained by the fact that studies showing higher rates of adverse events (52) used check lists actively asking the patient for the presence or absence of various symptoms. Some of these studies were reference-controlled, thereby carrying over higher adverse event rates from the synthetic antidepressant that is known by patients and investigators to bring about more side effects than SJW. In this study, patients were interviewed at each visit for adverse events in an open question procedure to avoid numerous reports of multiple disease-related symptoms. Investigators may have reported only adverse events not recognized as typical symptoms of disease. Thus, "adverse events" in our study may be better characterized as "suspected adverse drug reactions."

Since the design and sample size of this study is similar to that of a previous SJW trial (36) and another trial investigating opipramol in somatoform disorders (22), results can be compared reasonably. Regarding baseline HAMA-SOM values, patients in our trial were somewhat less severely affected than in the two other trials, probably at least in part due to the requirement of a maximum SOMS-7 inclusion score of 30. Adjusting 6-week outcome for these baseline differences by looking at the percent changes from baseline of HAMA-SOM, a mean effect of a approximately 55% decrease in HAMA-SOM scores can be seen for active treatments in all three trials. Placebo response rates, however, were significantly different between trials; percent changes from baseline of HAMA-SOM were about 23%, 34%, and 46% in the previous SJW study, in this trial, and in the opipramol trial, respectively. Similar observations are valid for the SCL-90-R-SOM results. Thus, effect sizes of the two SJW trials are of significant clinical relevance, which cannot be stated unambiguously for the opipramol trial. Are there any further differences between the trials that may explain different outcomes? Higher figures in baseline severity of illness in the opipramol study are unlikely to account for substantial placebo response, since patients in the previous SJW trial had similar baseline figures, and severity of illness is known to be inversely correlated with placebo response in drug trials in psychiatric disorders (53). A HAMD score of up to 24 was allowed in the opipramol trial, leading to baseline values of 14.6 (opipramol) and 14.3 (placebo), whereas thresholds of 14 and 12 ended up in mean baseline scores of 10.6 (SJW) and 10.8 (placebo) and 9.2 (both groups) in the previous and our SJW trial, respectively. Thus, comorbid depressive symptomatology was substantially higher in the opipramol trial, and results may reflect rather antidepressant activity of this drug than a significant effect on somatic symptoms not attributed to depression.

Not all antidepressants may be generally effective in somatoform disorders. In a large twin study, somatic distress has been shown to be a dimension psychologically, genetically, and environmentally distinct from anxiety and depression (54,55). Therefore, a differential treatment of these syndromes may be required. In a previous SJW trial (36) as well as in the present one, the improvement of somatization was independent from the presence or absence of depression; patients without relevant depressive symptomatology at baseline showed treatment response comparable to patients with more pronounced depressive symptomatology. However, HAMD had only been assessed at baseline to exclude patients more severely depressed, therefore a correlation of improvement of somatization with that of depression cannot be ruled out in this study.

Syndromal and genetic differences between somatization and depression would also implicate distinct underlying biological phenomena. One may be related to differential dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. Studies investigating HPA axis activity in somatoform and related disorders such as fibromyalgia and chronic fatigue syndrome show that these disorders are significantly different from melancholic depression with respect to the underlying neurobiology (56). Somatoform spectrum disorders may be related rather to DSM-IV "atypical depression" by showing a decrease in HPA axis activity compared with an increase in more severe types of depression (56,57). Against this background, recently a placebo-controlled trial has been initiated to examine the efficacy of SJW LI 160 in atypical depression. A similar downregulation of HPA axis activity has been observed in patients suffering from posttraumatic stress disorder (PTSD) (58). Interestingly, a history of traumatic life events is frequently associated with the development of somatoform disorders (59,60), pointing to a common etiology of these disorders. These findings may therefore be suggestive for SJW treatment of PTSD.

Immunological differences between major depression and somatization syndrome have also been reported: decreased soluble suppressor/cytotoxic antigen (CD8) and interleukin-6, and increased Clara cell protein (CC16) suggest a lowered T-lymphocytic activity in somatization syndrome when compared with depressed patients (61). Finally, activation of the HPA axis in the Dex-CRH challenge test, paralleled by response to treatment with SJW LI 160, has been demonstrated in non-melancholically depressed outpatients (62), which is in reverse to the action of other antidepressants in an inpatient setting (63,64). Altogether, SJW may exhibit a specific activity in non-melancholic depression and somatoform and related disorders (56).

CBT is widely accepted as an effective treatment for patients with somatization or symptom syndromes. Benefits can occur whether or not psychological distress is ameliorated (10,65–67). However, the superior cost-effectiveness of an effective herbal agent such as SJW or a conventional antidepressant drug, when compared with CBT with its requirement for close and frequent therapeutic sessions, warrants a comparative trial between both treatment strategies (68). However, design and performance would be rather complex, since the patients’ interaction and relationship with the treating physician will be a factor, which will confound outcomes in both treatment arms. Taking advantage of the great patients’ acceptance of the herbal SJW, the combined therapy SJW and CBT may hypothetically result in a better treatment response.

In this study, we have aimed to map everyday life in primary care as close as possible, since somatoform disorders represent significant psychiatric morbidity in nonpsychiatric settings (9). The deployment of more experienced raters, eg, in a psychiatric clinic, may have added some validity to the ratings; on the other hand, it may have reduced the generalizability of results due to the more artificial setting. Patients suffering from significant depression were excluded for methodological reasons, although depression and anxiety are known to frequently coexist with somatization syndromes (69). However, patients being additionally depressive may have well profited from the antidepressant action of SJW. Further, efficacy of SJW treatment on comorbid anxiety is reflected by the improvement on the HAMA-PSY subscale in this study, and antianxiety action of SJW has been suggested from case reports and subgroup analyses of depression trials (70–72). Efficacy conclusions from this trial cannot be extrapolated automatically to patients suffering from more severe and more chronic somatization syndromes. It further remains open whether 600 mg of SJW daily is the optimal dose and if higher dosages may result in increased efficacy. Moreover, future studies should investigate if extended treatment may further improve the outcome and if treatment effects can be preserved beyond the end of acute treatment or if subsequent maintenance therapy will be necessary.

Finally, it is suggested from the results of this and the trial by Volz et al. that SJW LI 160 may be a useful therapeutic alternative in the acute treatment of mildly to moderately severe somatoform disorders. Its excellent tolerability profile and patients’ generally positive attitude toward herbs offer various advantages when compared with other drug treatments.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
The study was funded by a grant from Lichtwer Pharma GmbH, Berlin, Germany.

We thank Winfried Rief who scientifically advised the study and helped with the manuscript. Richard W. Middleton of Medicherb UK Ltd, Marlow, UK, was a great help in proofreading and improving the linguistic quality of the manuscript.

We further acknowledge the commitment of the investigators and the staffs of the clinical study sites: Hüntemann R, Mattern W, Schumann G (Bochum); Fritze UA, Michael HG, Urlea-Schön I (Siegen); Egry A, Müller-Schulzen M (Rüsselsheim); Wehrmann D, Zingler W (Freudenberg); Finkernagel H (Bad Berleburg); Gnisa P (Pulheim); Kather-Volkov A (Köln); Peltz J (Hattingen); Radermacher E (Steinfurt-Borghorst); Steinhauer J (Weilmünster); Walther KU (Karlsruhe); Weidemann J (Bad Laasphe); Winter HH (Leverkusen); Wiswedel H (Fürth). And of course we are indebted to the 184 patients who participated in the study.

Received for publication July 15, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. (DSM-IV). Washington, DC: American Psychiatric Association; 1994.
  2. World Health Organization. The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: WHO; 1992.
  3. Hiller W, Rief W, Fichter M. How disabled are patients with somatoform disorders? Gen Hosp Psychiatry 1997; 19: 432–8.[CrossRef][Medline]
  4. Smith GR, Monson RA, Ray DC. Patients with multiple unexplained symptoms. Their characteristics, functional health, and health care utilisation. Arch Intern Med 1986; 146: 69–72.[Abstract]
  5. Bhui K, Hotopf M. Somatization disorder. Br J Hosp Med 1997; 58: 145–9.[Medline]
  6. Escobar JI, Rubio-Stipec M, Canino G, Karno M. Somatic symptom index (SSI): a new and abridged somatization construct. Prevalence and epidemiological correlates in two large community samples. J Nerv Ment Dis 1989; 177: 140–6.[CrossRef][Medline]
  7. Kroenke K, Spitzer RL, deGruy FV 3rd, Hahn SR, Linzer M, Williams JB, Brody D, Davies M. Multisomatoform disorder. An alternative to undifferentiated somatoform disorder for the somatizing patient in primary care. Arch Gen Psychiatry 1997; 54: 352–8.[Abstract]
  8. Rief W, Hessel A, Braehler E. Somatization symptoms and hypochondriacal features in the general population. Psychosom Med 2001; 63: 595–602.[Abstract/Free Full Text]
  9. Bass C, Peveler R, House A. Somatoform disorders: severe psychiatric illnesses neglected by psychiatrists. Br J Psychiatry 2001; 179: 11–4.[Abstract/Free Full Text]
  10. Kroenke K, Swindle R. Cognitive-behavioral therapy for somatization and symptom syndromes: a critical review of controlled clinical trials. Psychother Psychosom 2000; 69: 205–15.[CrossRef][Medline]
  11. Volz HP, Stieglitz RD, Menges K, Möller HJ. Somatoform disorders – diagnostic concept, controlled clinical trials, and methodological issues. Pharmacopsychiat 1994; 27: 231–7.
  12. Ferreri M, Florent C, Gerard D. Sulpiride: study of 669 patients presenting with pain of psychological origin. Encephale 2000; 26: 58–66.[Medline]
  13. Turkington D, Grant JB, Ferrier IN, Rao NS, Linsley KR, Young AH. A randomized controlled trial of fluvoxamine in prostatodynia, a male somatoform pain disorder. J Clin Psychiatry 2002; 63: 778–81.[Medline]
  14. Garcia-Campayo J, Sanz-Carillo C. Topiramate as a treatment for pain in multisomatoform disorder patients: an open trial. Gen Hosp Psychiatry 2002; 24: 417–21.[CrossRef][Medline]
  15. Fallon BA, Liebowitz MR, Salman E, Schneier FR, Jusino C, Hollander E, Klein DF. Fluoxetine for hypochondriacal patients without major depression. J Clin Psychopharmacol 1993; 13: 438–41.[Medline]
  16. Kjernisted KD, Enns MW, Lander M. An open-label clinical trial of nefazodone in hypochondriasis. Psychosomatics 2002; 43: 290–4.[Abstract/Free Full Text]
  17. Perugi G, Giannotti D, Di Vaio S, Frare F, Saettoni M, Cassano GB. Fluvoxamine in the treatment of body dysmorphic disorder (dysmorphophobia). Int Clin Psychopharmacol 1996; 11: 247–54.[Medline]
  18. Hollander E, Allen A, Kwon J, Aronowitz B, Schmeidler J, Wong C, Simeon D. Clomipramine vs desipramine crossover trial in body dysmorphic disorder: selective efficacy of a serotonin reuptake inhibitor in imagined ugliness. Arch Gen Psychiatry 1999; 56: 1033–9.[Abstract/Free Full Text]
  19. Phillips KA, Albertini RS, Rasmussen SA. A randomized placebo-controlled trial of fluoxetine in body dysmorphic disorder. Arch Gen Psychiatry 2002; 59: 381–8.[Abstract/Free Full Text]
  20. Noyes R Jr., Happel RL, Muller BA, Holt CS, Kathol RG, Sieren LR, Amos JJ. Fluvoxamine for somatoform disorders: an open trial. Gen Hosp Psychiatry 1998; 20: 339–44.[CrossRef][Medline]
  21. Menza M, Lauritano M, Allen L, Warman M, Ostella F, Hamer RM, Escobar J. Treatment of somatization disorder with nefazodone: a prospective open-label study. Ann Clin Psychiatry 2001; 13: 153–8.[CrossRef][Medline]
  22. Volz HP, Möller HJ, Reimann I, Stoll KD. Opipramol for the treatment of somatoform disorders - results from a placebo-controlled trial. Eur Neuropsychopharmacol 2000; 10: 211–7.[Medline]
  23. Dwight MM, Arnold LM, O’Brien H, Metzger R, Morris-Park E, Keck PE. An open clinical trial of Venlafaxine treatment of fibromyalgia. Psychosomatics 1998; 39: 14–7.[Abstract/Free Full Text]
  24. Engel CC, Walker EA, Engel AL, Bulls J, Armstrong A. A randomized, double-blind crossover trial of sertraline in women with chronic pelveic pain. J Psychosom Res 1998; 44: 203–7.[CrossRef][Medline]
  25. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Do antidepressants have an analgesic effect in psychogenic pain and somatoform pain disorder? A meta-analysis. Psychosom Med 1998; 60: 503–9.[Abstract/Free Full Text]
  26. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder. Arch Gen Psychiatry 1999; 56: 932–9.[Abstract/Free Full Text]
  27. Linde K, Mulrow CD. St John’s wort for depression (Cochrane Review). In: The Cochrane library. Issue 5. Oxford: Update Software; 2003.
  28. Bilia AR, Gallori S, Vincieri FF. St. John’s wort and depression. Efficacy, safety and tolerability – an update. Life Sci 2002; 70: 3077–96.[CrossRef][Medline]
  29. Sommer H, Harrer G. Placebo-controlled double-blind study examining the effectiveness of an hypericum preparation in 105 mildly depressed patients. J Geriatr Psychiatry Neurol 7( suppl 1): 9–11, 1994.
  30. Woelk H, Burkard G, Grünwald J. Benefits and risks of the hypericum extract LI 160: drug monitoring study with 3,250 patients. J Geriatr Psychiatry Neurol 7( suppl 1): 34–8, 1994.
  31. Woelk H, for the Remotiv/Imipramine study group. Comparison of St. John’s wort and imipramine for treating depression: randomised controlled trial. BMJ 2000; 321: 536–9.[Abstract/Free Full Text]
  32. Grube B, Schermuck S, Hopfenmüller W, Michel F. Use of a hypericum extract in mild, transient depressive disorders. Eur J Clin Res 1997; 9: 293–302.
  33. Stevinson C, Dixon M, Ernst E. Hypericum for fatigue – a pilot study. Phytomedicine 1998; 5: 443–7.
  34. Stevinson C, Ernst E. A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome. Br J Obstet Gynaecol 2000; 107: 870–6.
  35. Grube B, Walper A, Wheatley D. St. John’s wort extract: efficacy for menopausal symptoms of psychological origin. Adv Ther 1999; 16: 177–86.[Medline]
  36. Volz HP, Murck H, Kasper S, Möller HJ. St. John’s wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial. Psychopharmacology 2002; 164: 294–300.[CrossRef][Medline]
  37. Rief W, Hiller W. A new approach to assess treatment effects in somatoform disorders. Psychosomatics 2003; 44: 492–8.[Abstract/Free Full Text]
  38. Hiller W, Zaudig M, Mombour W, Bronisch T. Routine psychiatric examinations guided by ICD-10 Diagnostic Checklists (International Diagnostic Checklists). Eur Arch Psychiatry Clin Neurosci 1993; 242: 218–23.[CrossRef][Medline]
  39. Hiller W, Zaudig M, Mombour W. IDCL: International diagnostic checklists for ICD-10 and DSM-IV. Seattle: Hogrefe & Huber; 1996.
  40. Hiller W, von Bose M, Dichtl G, Agerer D. Reliability of checklist-guided diagnoses for DSM-IIIR affective and anxiety disorders. J Affect Disord 1990; 20: 235–47.[CrossRef][Medline]
  41. Rief W, Heuser J, Mayrhuber E, Stelzer I, Hiller W, Fichter MM. The classification of multiple somatoform symptoms. J Nerv Ment Dis 1996; 184: 680–7.[CrossRef][Medline]
  42. Rief W, Hiller W, Heuser J. SOMS – Das screening für somatoforme störungen; manual zum fragebogen. [SOMS-the screening for somatoform diaorders] Bern: Verlag Hans Huber; 1997.
  43. Rief W, Greitemeyer M, Fichter MM. Die symptom check list SCL-90-R: überprüfung an 900 psychosomatischen Patienten. Diagnostika 1991; 37: 58–65.
  44. Lehmann EL. Nonparametrics. Statistical methods based on ranks. New Jersey: Prentice Hall; 1998.
  45. European Agency for the Evaluation of Medicinal Products (EMEA); Committee for Proprietary Medicinal Products (CPMP). Note for Guidance on Statistical Principles for Clinical Trials (CPMP/ICH/363/96). London: EMEA; 18 March 1998.
  46. Wei LJ, Lachin JM. Two-sample asymptotically distribution-free tests for incomplete multivariate observations. J Am Stat Assoc 1984; 79: 653–61.[CrossRef]
  47. Thall PF, Lachin JM. Analysis of recurrent events: Nonparametric methods for random interval count data. J Am Stat Assoc 1988; 83: 339–47.[CrossRef]
  48. Lachin JM. Some large-sample distribution-free estimators and tests for multivariate partially incomplete data from two populations. Stat Med 1992; 11: 1151–70.[Medline]
  49. Maurer W, Hothorn LA, Lehmacher W. Multiple comparisons in drug clinical trials and pre-clinical assays: a-priori ordered hypotheses. In: Vollmar J, editor. Biometrie in der chemisch-pharmazeutischen Industrie 6. Stuttgart: Gustav Fischer; 1995.
  50. Colditz GA, Miller JN, Mosteller F. Measuring gain in the evaluation of medical technology. The probability of a better outcome. Int J Technol Assess Health Care 1988; 4: 637–42.[Medline]
  51. Kroenke K, Mangelsdorff D. Common symptoms in ambulatory care: incidence, evaluation, therapy and outcome. Am J Med 1989; 86: 262–6.[CrossRef][Medline]
  52. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s wort) in major depressive Disorder: a randomized controlled trial. JAMA 2002; 287: 1807–14.[Abstract/Free Full Text]
  53. Montgomery SA. The failure of placebo-controlled studies. ECNP Consensus Meeting, September 13, 1997, Vienna. European College of Neuropsychopharmacology. Eur Neuropsychopharmacol 1999; 9: 271–6.[Medline]
  54. Gillespie N, Kirk KM, Heath AC, Martin NG, Hickie I. Somatic distress as a distinct psychological dimension. Soc Psychiatry Psychaitr Epidemiol 1999; 34: 451–8.
  55. Gillespie NA, Zhu G, Heath AC, Hickie IB, Martin NG. The genetic aetiology of somatic distress. Psychol Med 2000; 30: 1051–61.[CrossRef][Medline]
  56. Murck H. Atypical depression spectrum disorder - neurobiology and treatment. Acta Neuropsychiatrica 2003; 15: 227–41.[CrossRef]
  57. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 2002; 53: 865–71.[CrossRef][Medline]
  58. Yehuda R. Biology of posttraumatic stress disorder. J Clin Psychiatry 2001; 62( suppl 17): 41–6.
  59. Andreski P, Chilcoat H, Breslau N. Post-traumatic stress disorder and somatization symptoms: a prospective study. Psychiatry Res 1998; 79: 131–8.[CrossRef][Medline]
  60. Breslau N. Outcomes of posttraumatic stress disorder. J Clin Psychiatry 2001; 62( suppl 17): 55–9.
  61. Rief W, Pilger F, Ihle D, Bosmans E, Egyed B, Maes M. Immunological differences between patients with major depression and somatization syndrome. Psychiatry Res 2001; 105: 165–74.[CrossRef][Medline]
  62. Holsboer-Trachsler E, Brand S, Hatzinger M, Hemmeter U. Effects on hypericum extract on sleep EEG and Dex/CRH test in patients with depression. Biol Psychiatry 2001; 49: 9S.
  63. Nickel T, Sonntag A, Schill J, Zobel AW, Ackl N, Brunnauer A, Murck H, Ising M, Yassouridis A, Steiger A, Zihl J, Holsboer F. Clinical and neurobiological effects of tianeptine and paroxetine in major depression. J Clin Psychopharmacol 2003; 23: 155–68.[CrossRef][Medline]
  64. Zobel AW, Nickel T, Sonntag A, Uhr M, Holsboer F, Ising M. Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. A prospective study. J Psychiatr Res 2001; 35: 83–94.[CrossRef][Medline]
  65. Allen LA, Woolfolk RL, Lehrer PM, Gara MA, Escobar JI. Cognitive behavior therapy for somatization disorder: a preliminary investigation. J Behav Ther Exp Psychiatry 2001; 32: 53–62.[CrossRef][Medline]
  66. Kendall PC, Pimentel SS. On the physiological symptom constellation in youth with Generalized Anxiety Disorder (GAD). J Anxiety Disord 2003; 17: 211–21.[CrossRef][Medline]
  67. Looper KJ, Kirmayer LJ. Behavioral medicine approaches to somatoform disorders. J Consult Clin Psychol 2002; 70: 810–27.[CrossRef][Medline]
  68. Hiller W, Fichter MM, Rief W. A controlled treatment study of somatoform disorders including analysis of healthcare utilization and cost-effectiveness. J Psychosom Res 2003; 54: 369–80.[CrossRef][Medline]
  69. Allen LA, Gara MA, Escobar JI, Waitzkin H, Silver RC. Somatization: a debilitating syndrome in primary care. Psychosomatics 2001; 42: 63–7.[Abstract/Free Full Text]
  70. Davidson JR, Connor KM. St. John’s wort in generalized anxiety disorder: three case reports. J Clin Psychopharmacol 2001; 21: 635–6.[CrossRef][Medline]
  71. Friede M, Wüstenberg P. Johanniskraut zur Therapie von Angstsyndromen bei depressiven Verstimmungen. Ztschr Phytother 1998; 19: 309–17.
  72. Kasper S, Dienel A. Cluster analysis of symptoms during antidepressant treatment with Hypericum extract in mildly to moderately depressed out-patients. A meta-analysis of data from three randomized, placebo-controlled trials. Psychopharmacology 2002; 164: 301–8.[CrossRef][Medline]



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