Diagnostic features of the cycloid psychoses in a first psychotic episode sample

Methods Seventy patients diagnosed with one-year first schizophrenia episode, schizophreniform disorder, or schizoaffective disorder were studied (mean age, 27.9 years old; SD ± 6.34). The detection of the possible cases of cycloid psychosis was done according to the Perris and Brockington operational criteria. Two groups of “cycloid” ( n = 11) and “non cycloid” ( n = 59) patients were compared according to demographic and clinical variables, and possible diagnostic variables were evaluated by the ROC curves. Results Significant differences were found between cycloid and non cycloid groups for a number of clinical variables: prodromic symptoms ( p < 0.001), PANSS total score ( p = 0.003), PANSS-P ( p = 0.009), PANSS-GP ( p = 0.001), total score for mania by EVMAC ( p = 0.001), and CDSS for depression ( p = 0.004). ROC curves were significant for PANSS-GP (AUC = 0.791, p = 0.002), EVMAC (AUC = 0.938, p = 0.001), and CDSS (AUC = 0.770, p = 0.005). A sensitivity/specificity study demonstrated a negative predictive value for PANSS-GP (93.88%), EVMAC (96.30%), and CDSS (93.88%). Conclusions According to these results, cycloid psychoses might represent differentiated and well-defined clinical entity. Keywords Affective disorders Cycloid psychoses Diagnosis First episode Schizophrenia 1 Introduction The cycloid psychosis is a diagnostic concept that has been gradually developed for the last 120 years in Europe. Such a concept includes some acute, recurrent, and benign psychotic disorders whose symptoms are neither typically affective nor schizophrenic but basically polymorphous. The first diagnostic criteria for cycloid psychoses were described by Leonhard, who made an exhaustive clinical description and concluded that this concept represents a group of acute and self-limited psychotic disorders that could be diagnosed on the base of a transversal evaluation of the clinical features and are presented in three clinical subtypes (anxiety-beatific, excited–inhibited confusion, and hyperkinetic–akinetic motility dysfunction forms) ( Leonhard, 1962 ). Afterwards, Perris and Brockington developed the first operational diagnostic criteria to describe the disorder ( Perris, 1988 ), which are currently the most used ones ( Peralta et al., 2007 ). These criteria are the following: 1) acute psychosis not related to drug consumption and without organic base, first episode between 15–50 years old; 2) sudden onset with a rapid progression to psychosis; 3) presence of at least four of the following inclusion criteria—confusion, mood-incongruent, delusions of any type, hallucinations of any type, overwhelming anxiety (psychotic anxiety), intense feelings of happiness or ecstasy, motility disturbances either akinetic or hyperkinetic, a concern with death, and mood swings; and 4) there is not a specific combination but symptomatology can frequently change showing a bipolar character. Unlike the first diagnostic criteria described by Leonhard, the Perris and Brockington criteria represent a “collection of symptoms,” ( Peralta et al., 2007 ), where the overlapping of symptoms is the rule and thus a classification into subtypes would not be appropriate. Afterwards, several authors ( Sigmund and Mundt, 1999; Pfuhlmann et al., 2004; Jabs et al., 2006 )pointed out that the complete development of a maniac or depressive syndrome would be an exclusion criterion, but this idea has been strongly refuted ( Peralta et al., 2007 ); even some authors affirmed that such a syndrome is part of an affective disorder ( Cutting, 1990 ). Recently, guides for the diagnosis of the disorder and its features have been developed but their reliability and validity have not been studied yet by authors ( Sigmund and Mundt, 1999; Pfuhlmann et al., 2004 ). Despite the clinical, prognostic, and therapeutic relevance of the cycloid psychoses, the current nosological systems have conferred little importance to the diagnosis and clinical validity of these syndromes. The studies that have examined empirically the nosological relation between the cycloid psychoses and the consensus criteria have consistently shown that the cycloid psychoses do not correspond with any category in DSM-IV and CIE-10 ( Maj, 1988; Zaudig, 1990; Beckmann et al., 1990; Peralta and Cuesta, 2003a,b; Peralta et al., 2007 ). As a result, the majority of the cycloid psychoses are diagnosed within these systems as brief reactive psychosis, schizophreniform disorder, schizoaffective disorder, non-specific psychotic disorder, or mood disorder with psychotic symptoms ( Peralta and Cuesta, 2003a,b ). The objectives of the current study were to detect cycloid psychoses cases in a sample of patients who present a first psychotic episode and to analyze the clinical validity of the cycloid psychoses by comparing both groups (“cycloid” and “non cycloid”). Afterwards, potential evaluation tools for diagnosis were analyzed. 2 Materials and methods A total number of 70 patients hospitalized in an acute unit of a general hospital between 2004 and 2008 were included in the study. The patients presented a first psychotic episode (FPE) according to the DSM-IV diagnostic criteria for schizophreniform disorder, schizoaffective disorder, or schizophrenia. The classifications of the axis I of DSM-IV were evaluated by MINI-Plus. The inclusion criteria were the following: 1) hospitalized patients who present a first psychotic episode according to the DSM-IV criteria; 2) patients aged 18–65 years; and 3) patients must be able to give informed consent (or their first-degree relatives). The exclusion criteria were the following: 1) acute psychotic episode due to the use of toxic substances; 2) brief psychotic episode; 3) psychotic episode due to known medical disease (e.g. history of head trauma, cerebrovascular disease, infections, etc.); and 4) vital history of dependence to substances according to the DSM-IV criteria. Each patient was thoroughly studied by appropriate medical history, physical exploration, and laboratory tests to comply with the inclusion criteria. In addition to the requirements mentioned above, patients were informed clearly and extensively about the characteristics of the study so all of them gave their informed consent. Patients were included and assessed when they were hospitalized and discharged. The detection of the possible cases of cycloid psychosis was done by applying the operational criteria for the diagnosis of cycloid psychosis by Perris and Brockington. Afterwards, the sample was divided into two groups, “cycloid” ( n = 11) and “non cycloid” ( n = 59), according to the diagnostic criteria used. The average age of the patients was 27.9 years old (minimum 18 years, maximum 42 years old, SD ± 6.34). Regarding sex, 51.4% were men while 48.6% were women. In relation to the prodromal symptoms, which are described as not very frequent in the literature ( Barcia and Morcillo, 1996; Barcia, 1998 ), dysphoria and sleep disturbances were assessed and measured as the number of days that the symptoms are present (or not) until the psychosis acme. Regarding the duration of untreated psychosis (DUP), a definition was used according to the recommendations given by Bromet et al. ( 1992 ). A semi-structured interview was done with the patients and their relatives to gather data regarding the chronology of the first psychotic symptoms. After analyzing the data, the time of the psychotic disorder course, in days, was established for each case and the initial age of the patient at the debut of the disease was calculated ( Larsen et al., 2000 ). The DUP median, in days, was 60 (IQR, 15–120). The mean initial age at the debut of the disease was 27.4 years old (SD ± 6.3). The type of disease onset was defined as acute (less than 6 months) or insidious (more or equal to 6 months), in relation to the time passed since the detection of any of the prodromal symptoms (i.e. symptoms that, despite belonging to the positive, negative, or disorganized scales, were not sufficiently intense to be considered as diagnostic criteria) ( Woods et al., 2001 ). In order to assess the psychotic symptoms, the Positive and Negative Symptom Scale (PANSS) was used ( Peralta and Cuesta, 1994 ); this scale consists of 30 items and 3 subscales (PANSS-P-Positive, PANSS-N-Negative, and PANSS-GP-Global Psychopathology) and a scale of 7 points to assess the severity of each symptom. The tools used to assess the affective symptomatology were the following: 1) The Clinician-Administered Rating Scale for Mania (EVMAC, validated Spanish version), derived from Schedule for Affective Disorders and Schizophrenia, was used to assess the presence and severity of the maniform symptomatology ( Altman et al., 1994 ); this tool consists of 10 items (elevated mood/euphoria, irritability/aggressiveness, motor hyperactivity, push of speech, flight of ideas, distractibility, grandiosity, need for sleep, excessive energy, and impaired judgment) and some cut points recommended in the Spanish version ( Livianos et al., 2000 ), which allows categorizing patients in “no mania or questionable mania” (0–7), “mild manic symptomatology” (8–15), “moderate manic symptomatology” (16–25), and “severe manic symptomatology” (≥ 26). 2) The assessment of the depressive symptomatology was done by means of the Calgary Depression Scale for Schizophrenia (CDSS), which measures the level of depression of schizophrenic patients in acute phase; the scale consists of 9 items with a score that ranges from 0 to 27 points and some cut points (recommended in the Spanish version) ( Sarró et al., 2004 ) which allows differentiating patients with or without depression. Global functioning and severity of the psychotic episode were assessed by means of the Global Assessment of Functioning (GAF) Scale and the subscale Clinical Global Impression (CGI) Severity Scale, respectively. All the patients were treated with atypical antipsychotics (risperidone, ziprasidone, olanzapine, aripiprazole, and quetiapine). The antipsychotic dose at discharge was transformed into chlorpromazine equivalent dose according to Woods' recommendations ( Woods, 2003 ). Of all the patients, 42.9% were prescribed benzodiazepines at discharge from hospital, and the dose was transformed into clorazepate dipotassium equivalent dose. Discharge and hospitalization were also assessed and measured in days, and the median was 18 days (IQR, 13–28). In order to assess the response to treatment, the Improvement subscale of the Clinical Global Impression (CGI) Rating Scale was used; measurements were made at discharge. Moreover, patients were categorized as “responders” (1–2) and “non responders” (3–7). Prognosis was measured afterwards as “relapses” in the case of the patients who were re-hospitalized within the first year after the first psychotic episode. Qualitative variables were summarized by their frequency distribution, and quantitative variables, by their mean and ± SD. The continuous non-normally distributed variables were summarized by the median and interquartile range (IQR, 25–75). In case of qualitative variables, comparison was evaluated by the chi-square test or by the Fisher's exact test in case more than 25% of the expected values were less than 5. For quantitative variables, the Student's t -test or the non parametric Mann–Whitney U test was used to compare between the study groups. Receiver operator characteristics (ROC) analysis was calculated to assess the utility of the independent variables (PANSS-GP, EVMAC, and CDSS) to distinguish cycloid from non cycloid patients. Area under curve (AUC) and its 95% confidence intervals (CI) for ROC curves were calculated. Sensitivity, specificity, positive predictive values, and negative predictive values (PPV and NPV, respectively), and its 95% CIs were determined. For all of these tests, the significance level accepted was 5%. Process and analysis of the data was done through the statistical package SPSS version 15.0 for Windows (SPSS, Chicago, IL, USA). 3 Results No significant differences were found in age ( p = 0.15) and in age at onset ( p = 0.11) between the “cycloid” and “non cycloid” groups. Similarly, no significant differences were found between the two groups regarding sex; however, there is a higher tendency of cycloids in favor of women ( p = 0.07, χ 2 = 3.05). In relation to prodromal symptoms, significant differences were found between the two groups regarding the duration of dysphoria in days ( p = 0.001, u = 121.5) and in sleeping disorders ( p = 0.001, u = 189.5); the duration is longer in the “non cycloid” group than in the “cycloid” group with a median of 60 days (IQR, 15–120) against 4 days (IQR, 0–7) for dysphoria and a median of 60 days (IQR, 15–120) against 4 days (IQR, 4–30) for sleeping disorders, respectively. In relation to the duration of untreated psychosis (DUP) and the type of onset, considerable differences were also found between both groups ( Table 1 ). There are significant differences between “cycloid” and “non cycloid” groups in the following: total score in the Positive and Negative Symptoms Scale (PANSS), PANSS subscale for the assessment of positive symptoms (PANSS-P), and PANSS subscale for the assessment of general psychopathology (PANSS-GP); total score in the Clinician-Administered Rating Scale for Mania (EVMAC); presence or absence of mania categorized by EVMAC; total score in Calgary Depression Scale for Schizophrenia (CDSS); and presence or absence of depression categorized by CDSS ( Table 1 ). However, there were no significant differences ( p = 0.37; t = −0.085) in the PANSS subscale for the assessment of negative symptoms (PANSS-N). Similarly, there were significant differences between the two groups in the Global Assessment of Functioning (GAF) Scale ( Table 1 ). In the Clinical Global Impression (CGI) Scale, no significant differences were found ( p = 0.39; χ 2 = 4.92) in the Severity subscale but significant differences were found in the Improvement subscale ( Table 1 ). However, when the Improvement subscale was categorized in “responders” and “non responders,” no statistically significant differences were found ( p = 0.11; χ 2 = 3.25) between “cycloid” and “non cycloid.” No statistically significant differences between the two groups were found in the dose of antipsychotics (in chlorpromazine equivalent dose) administered at discharge ( p = 0.57; u = 284.50) being the median of the whole sample (300 mg; IQR, 200–425). Nevertheless, significant differences ( p = 0.001; u = 27.0) were found in the doses (in clorazepate dipotassium equivalent doses) of prescribed benzodiazepines at discharge (42.9% of all the samples) in the “cycloid” group (45 mg; IQR, 30–100) and in the “non cycloid” group (15 mg; IQR, 10–30). Considering “relapses,” no significant differences were found ( p = 1.00; χ 2 = 0.001) between “cycloid” (18.2%) and “non cycloid” (18.6%). In conclusion, significant differences were found in duration of prodromal symptoms in days (dysphoria, p = 0.001; sleeping disorders, p = 0.001), DUP ( p = 0.001), type of disease onset ( p = 0.002), PANSS total score ( p = 0.003), PANSS subscale for positive symptoms ( p = 0.009) and for general psychopathology ( p = 0.001), EVMAC total score for mania ( p = 0.001) and CDSS for depression ( p = 0.004), GAF scale for global functioning ( p = 0.004) and CGI Improvement subscale ( p = 0.002). The results of the ROC curves were the following: 1) PANSS-GP ( Fig. 1 ): AUC = 0.791, p = 0.002, reliability interval at 95% [0.620–0.963]; 2) EVMAC ( Fig. 2 ): AUC = 0.938, p = 0.001, reliability interval at 95% [0.883–0.994]; and 3) CDSS ( Fig. 3 ): AUC = 0.770, p = 0.005, 95% CI [0.615–0.924]. Afterwards, for each of the tools used to assess the affective and psychotic symptomatology, the cutoff points were selected in function of the ROC coordinates according to the best combination of sensitivity and specificity values. The following cut points were selected: 1) PANSS-GP score = 52 (sensitivity 0.727 and specificity 0.780); 2) EVMAC score = 16 (sensitivity 0.818 and specificity 0.881), which in turn is considered as the cut point for moderate mania; and 3) CDSS score = 7 (sensitivity 0.727 and specificity 0.780). Table 2 shows the sensitivity, specificity, positive predictive values, and negative predictive values for selected cutoffs for the three scales of study ( Table 2 ). 4 Discussion The group of patients taking part in this study was diagnosed with cycloid psychosis (according to the operational criteria described by Perris and Brockington), and they represent a homogeneous and well differentiated group from the rest of patients with first psychotic episodes. Considering the results from this study, the cycloid psychoses would present, according to the previous literature ( Leonhard, 1962; Perris, 1988; Maj, 1988; Peralta et al., 2007 ), as a well differentiated and defined clinical entity. Cycloid psychoses (CP) account for 15.7% of the total number of hospitalizations due to first psychotic episode, according to previous studies which estimated 10%–15% of cases of CP ( Peralta et al., 2007 ). Moreover, in the only epidemiologic study that has been done up to now, it is stated that the annual incidence rate for patients with first psychotic episode is 0.043 per 100,000 inhabitants, which represents almost 25% of all functional psychoses in patients under 50 years old ( Lindvall et al., 1993 ). The onset of the disease occurs during the second or third decade of life ( Lindvall et al., 1993> ), and there are no significant differences with other functional psychoses, being the mean age for the first psychotic episode is 27.4 years (SD ± 6.3). It tends to be more frequent in women ( Lindvall et al., 1993>; Peralta et al., 2007 ) (72.7% of the “cycloid” patients), but this difference is not statistically relevant regarding the other first psychotic episodes (“non cycloid”). Although some differences were found in cycloid patients regarding prodromal symptoms, such as dysphoria and sleeping disorders, the duration in days is significantly shorter than in the rest of first psychotic episode patients. Unlike brief reactive psychoses, our patients did not undergo an intense vital situation that could precipitate the episode. The presence of insidious prodromal and inexplicable symptoms is predictable as they are really schizophreniform disorders. The onset is acute and abrupt ( Perris, 1988 ), which explains why the antipsychotic treatment starts (expressed as DUP in days) with a median of 7 days (IQR, 4–7); however, it is still significantly lower to the rest of first psychotic episode cases. The symptomatology was, to a great extent, as it had been expected but with higher scores in the positive symptoms of the PANSS subscale than the non cycloid patients. However, significant differences were not observed in the presence and intensity of negative symptoms (measured with PANSS-N) in comparison with the other first psychotic episode patients. This observation contradicts the classical idea that the absence of negative symptoms differentiates the cycloid psychoses from schizophrenia ( Perris, 1988 ). The most significant differences between the cycloid psychoses and the other first psychotic episodes are in the general psychopathology (measured by the PANSS-GP), which can be obviously explained by the polymorphous symptomatology that defines them ( Perris, 1988 ). In previous studies, it was stated that almost 50% of the cycloid patients present a complete affective syndrome and the majority of the other patients present an incomplete affective syndrome ( Peralta and Cuesta, 2003a,b ). In our study, 100% of the cycloid patients presented relevant manic symptomatology and 81.8% presented significant depressive symptoms, characteristics that differentiate them from the other first psychotic episode patients in the sample. The presence of this affective syndrome in the cycloid patients was not only more frequent but also of higher intensity than in the non cycloid patients, according to the scales for affective syndromes used. Another interesting aspect of the results is the confirmation that the hospitalization time for the cycloid patients (despite being acute and abrupt) was not different from the other first psychotic episode patients (median, 18 days). However, the assessment of the functional deterioration in the GAF scale, according to the clinicians' criteria, was significantly worse for the cycloid patients; this result can be explained by the behavioral instability characteristic of this clinical picture. The improvement associated to treatment (measured with CGI Improvement subscale) was significantly better in the cycloid patients indicating that a higher frequency of complete remissions without residual symptoms or global deterioration. Nevertheless, there was not a better response to treatment, in terms of “responders” and “non responders,” among the cycloid patients; this could be due to the good initial response to treatment that most psychotic episodes show at the initial phases. The importance of these results lies in the possibility of improving the clinical interventions so as to establish prognosis and treatment. As there is not a categorical differentiation between the cycloid psychoses and the other first psychotic episodes, there are no specific guidelines for cycloid psychoses. Clinicians tend to treat these cases in a more conservative way in a long term due to the complete disappearance of the episode symptoms, and they normally do not prescribe a maintenance treatment. It is frequently used in some mood stabilization medications when the affective symptoms are present during the episode. These questions could be tackled if a specific category that allows defining some research criteria was established and validated. For this purpose, the scales PANSS-GP for general psychopathology, EVMAC for mania, and CDSS for depressions could be useful tools in the diagnosis of the cycloid psychosis due to their high predictive value, as shown by the results of this study. In this way, it is not possible to diagnose cycloid psychoses in those patients with scores below 52 in the PANSS-GP scale, of 16 in the EVMAC scale (which coincides with “presence of moderate mania”), and of 7 in the CDSS scale (which coincides with “presence of depression”) with a probability of 93.88%, 96.30%, and 93.88%, respectively. In some way, the cycloid psychoses seem to be brief psychoses of longer duration and with a different onset. This leads to the use of conservative treatments and the withdrawal of maintenance treatment. However, the idea of transient episode and complete recovery should be revised by means of specific studies for cognitive functions in cycloid patients and taking into account the data from prospective studies on the course of these pictures. As there are no studies on cycloid psychoses, there are no data on the course, frequency of relapses, and diagnostic variability on these patients along time and in subsequent exacerbations. The establishment of a category or a subcategory would allow the study of the relation of these clinical pictures with the mood disorders and the development of studies on specific treatments for cycloid patients. 5 Conclusions The results of this study suggest that the historical construct of cycloid psychosis has an empiric validity that differentiates it from other acute and subacute psychotic disorders. The heuristic value of this concept is important as it defines a specific syndrome with a characteristic clinical pattern regarding onset, presentation, and prognosis from the first vital episode of the disorder. Some assessment tools, such as the PANSS-GP subscale for psychotic symptoms, EVMAC scale for mania, and CDSS scale for depression seem to be useful for the diagnosis of the cycloid psychosis in the first psychotic episode due to the predictive negative value. It is necessary to recognize the concept of cycloid psychosis due to the clinical and prognostic implications involved as the “cycloid” patients are at risk of being incorrectly diagnosed with schizophrenia or brief acute psychosis when, in fact, they suffer from neither of them and they may be affected by the therapeutic repercussions. Consequently, the clinical relevance and the importance for research of this construct seem to indicate that it will be useful to include it as a distinctive category in future diagnostic manuals. Role of funding source There was not any sponsor in this study. Conflict of interest All authors declare that they have no conflicts of interest. Acknowledgments Thanks to Dr. Manuel Fuentes Ferrer, Department of Epidemiology at Cliníco San Carlos Hospital, Madrid (Spain), whose advice on experimental design and help with subsequent analysis were invaluable. References Altman et al., 1994 E.G. Altman D.R. Hedeker P.G. Janicak J.L. Peterson J.M. Davis The Clinician-Administered Rating Scale for Mania (CARS-M): development, reliability, and validity Biol. Psychiatry 36 2 1994 124 134 Barcia, 1998 D. Barcia Psicosis cicloides. Tricastela, Madrid (Spain). Spanish 1998 Barcia and Morcillo, 1996 D. Barcia L. 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