MD Ritva Erkolahti
email: ritva.erkolahti@satshp.fi

PhD, Docent Marjaana Nystro

Keywords:

The prevalence of transitional object use in adolescence: is there a connection between the existence of a transitional object and depressive symptoms?

Introduction

Infants and young children often form a strong attachment to soft objects, such as teddy-bears, blankets, pillows and dolls. Winnicott [START_REF] Winnicott | Transitional objects and transitional phenomena[END_REF][START_REF] Winnicott | Playing and reality[END_REF][START_REF] Winnicott | The maturational processes and the facilitating environment[END_REF][START_REF] Winnicott | The location of cultural experiences[END_REF] emphasizes the developmental significance of this attachment to what he calls a transitional object (TO).

Most studies of TOs and their developmental and psychological role have naturally dealt with infants and young children. There is, however, anecdotal evidence in support of the view that certain articles continue to play the role of a TO after childhood, and that the phenomenon is not uncommon among adolescents or even adults [START_REF] Arthern | How do transitional objects work? The client's view[END_REF]. In the investigation by Bacharr et al. [START_REF] Bacchar | Childhood vs. adolescence transitional object attachment, and its relation to mental health and parental bonding[END_REF] of TO attachment in normal adolescents, 22% of respondents reported that they were currently attached to a TO. In some studies, an obvious long-lasting attachment to a certain object and TO use in adolescence have been connected to a greater number of psychiatric symptoms and diminished general wellbeing [START_REF] Bacchar | Childhood vs. adolescence transitional object attachment, and its relation to mental health and parental bonding[END_REF][START_REF] Shafii | The prevalence and use of transitional objects: a study of 230 adolescents[END_REF]. Markt and Johnson [21] found a connection between TO use and depression, especially when the adolescents felt lonely and feared falling asleep. Taking into account the introvert, uncommunicative and non-cooperative nature of many adolescents, an easily observed marker, such as an attachment to an object, can be helpful and sometimes crucial in identifying mental distress in normal adolescents [START_REF] Bacchar | Childhood vs. adolescence transitional object attachment, and its relation to mental health and parental bonding[END_REF].

j Developmental and psychological meaning of transitional objects

According to Winnicott [START_REF] Winnicott | Transitional objects and transitional phenomena[END_REF][START_REF] Winnicott | The maturational processes and the facilitating environment[END_REF][START_REF] Winnicott | The location of cultural experiences[END_REF], the TO helps the infant to learn to understand life outside himself or herself: it plays a role as the first ''not me'' possession and helps the child to re-establish his/her union with the mother after the separation process. One significant role of a TO is to comfort and soothe in a situation of separation anxiety, when the child is physically and psychologically separated from the mother. By means of the TO the child relates to the mother symbolically [START_REF] Adler | The psychotherapy of core borderline psychopathology[END_REF][START_REF] Mahler | The psychological birth of the human infant: symbiosis and individuation[END_REF]. According to Bowlby [START_REF] Bowlby | Attachment and loss[END_REF], the child creates an ''internal working model'', i.e. a schema of the attachment object, which can be activated whenever the primary person is absent. Winnicott [START_REF] Winnicott | Playing and reality[END_REF][START_REF] Winnicott | The maturational processes and the facilitating environment[END_REF][START_REF] Winnicott | The location of cultural experiences[END_REF] considers a child's attachment to a TO to be normal, universal and even necessary for healthy development; he reports a number of clinical case histories in which subsequent psychopathology was related to the absence of TO use in childhood. There are also contrary opinions, such as that of Brody [START_REF] Brody | Idealization of a phenomenon[END_REF], who questions the function and the role of a TO and considers that its developmental and psychological meaning has been misunderstood. TO use also seems to be influenced by social and/ or cultural factors: it is more common in western countries and urban areas, where children generally sleep alone and do not have close physical contact with the mother in the course of daily activities, than in countries where infants have close physical contact with the mother [START_REF] Daws | Feeding problems and relationship difficulties: therapeutic work with parents and infants[END_REF][START_REF] Gaddini | Transitional objects and the process of individuation: a study in three different social groups[END_REF][START_REF] Hong | Infants' attachments to inanimate objects. A cross cultural study[END_REF].

The connection between breastfeeding and TO use shows similar trends to those observed for TO use and physical contact with the mother. Breastfed infants did not use TOs as often as those fed on bottled milk. The duration of breastfeeding also affected the use of a TO: children with a long-lasting breastfeeding period (over 8 months) did not use a TO as often as those with a shorter one. TOs appeared when breastfeeding ended [START_REF] Ikeuchi | Social psychological determinants of appearance of transitional objects: focusing of nursing environment[END_REF][START_REF] Tabin | Transitional objects as objectifiers of the self in toddlers and adolescents[END_REF][START_REF] Viberg | Nallen I psykologi. En prospektiv studie med focus pa ˚barns anva ¨nding av o ¨verga ˚ngsobjekt[END_REF].

The fate of the TO seems to be to lose its comforting role as the infant grows: the attachment diminishes gradually after the third birthday, or at the latest when the child begins school [START_REF] Winnicott | Playing and reality[END_REF].

A study of treasured objects in school-aged children indicated that approximately half of all children between 9 and 13 years of age had formed an attachment to an object in infancy. About half of them kept it until the age of 9 years. There were no significant behavioural differences between those children who were attached to an object and those who were not [START_REF] Sherman | Treasured objects in school-aged children[END_REF].

Prolonged use of a TO into adolescence and adulthood may indicate psychopathology. Research with clinical populations has shown that TO use occurs mostly among individuals with borderline personality disorder [START_REF] Cardasis | Transitional objects and borderline disorder[END_REF][START_REF] Laporta | Borderline personality disorder and transitional objects[END_REF][START_REF] Morris | Transitional object use and borderline psychopathology[END_REF]. In a study by Cardasis et al. [START_REF] Cardasis | Transitional objects and borderline disorder[END_REF], the connection between possession of a TO and a borderline personality disorder diagnosis was investigated in a psychiatric inpatient setting. Significantly more patients who reported having TOs in the hospital or at home had a diagnosis of borderline personality disorder. It is suggested that these individuals lack a sense of object constancy [START_REF] Cardasis | Transitional objects and borderline disorder[END_REF]. According to Adler [START_REF] Adler | The psychotherapy of core borderline psychopathology[END_REF], a major problem lies in borderline patients' inability to rely on their own internal resources to maintain and comfort themselves when faced with separation. These difficulties are related to their feelings of solitude, their problems with a vulnerable evocative memory and a tenuous capacity to maintain holding and soothing introjections of important people when experiencing the stress of separation. Bacchar et al. [START_REF] Bacchar | Childhood vs. adolescence transitional object attachment, and its relation to mental health and parental bonding[END_REF] studied childhood versus adolescence TO use and found out that the use of a TO in adolescence was significantly related to psychopathology and reduced general wellbeing. In a study of college-age students, the use of TOs and a fear of falling sleep showed a statistically significant correlation with depression [START_REF] Markt | Transitional objects, pre-sleep rituals, and psychopathology[END_REF].

j Purpose of the study

In this study, we define a TO as any object which has a special value as a means of comforting and reducing anxiety -whether in childhood or in adolescence. We assume that the years of adolescence are so close to childhood that it is not unusual to be attached to an object; this is partly a normal phenomenon-the propensity to endow a certain object with the role of a TO as a comforting element. We hypothesize that particularly in those cases where the developmental process from childhood to adolescence involves problems, the previously experienced comforting and maintaining function of a TO may recur and the unusual relationship to the article playing the role of a TO may persist longer.

The purpose of the study was to investigate the prevalence of TO use in adolescence generally and according to gender, and the connection between depressive symptoms and TO use among adolescent boys and girls.

Permission for the study was granted by the Ethics Committee of the City of Turku and by the Turku School Board.

Method j Subjects

A total of 1,675 eighth-grade Finnish-speaking Caucasian students (794 boys and 881 girls) were recruited from normal comprehensive schools in the city of Turku, South-West Finland, with approximately 175,000 inhabitants. International schools, non-Caucasian students and schools with Swedishspeaking students were excluded. The response rate was 82.5%, i.e. 1,415 forms were handed in. From these we excluded those which were left blank, gave incomplete background data (including the respondent's gender), or included non-serious answers. The total number of subjects excluded due to incomplete data was 361 (25.5%). The resulting study group consisted of 1,054 adolescents: 465 boys and 589 girls. This group included 62 subjects (30 boys and 32 girls) who filled in the CDI questionnaire (children's depression inventory) but did not answer the question about TOs. This group did not differ from the main study group with respect to age, sex or the mean of CDI scores. The final sample of 992 subjects represents 70% of the eighth-grade students who handed in the forms and 60% of all eight-grade students in the normal Finnish-speaking comprehensive schools in the city of Turku.

The mean age of the respondents was 14.5 years (SD 0.50) for boys and 14.5 years (SD 0.51) for girls. The participants were more or less evenly distributed across social classes within the area of Turku. The subjects' social class was defined in terms of the guardian's occupation.

j Procedure and measures

The study was carried during a normal school day. The anonymous questionnaires were distributed in the classroom in the presence of a teacher, and all the students who were in the class were invited to answer a questionnaire on background data, one on TO questions, and a separate CDI questionnaire.

Information on TOs was elicited with two questions. In the first, the student was asked to answer yes or no to the question ''Do you currently have a special favourite article that you keep with you when you sleep, when you are away from home for some reason, or when you are traveling at home or abroad-for instance a soft animal, teddy-bear, doll, pillow, blanket or an other article?'' If the answer was yes, in the next question the student was asked to specify what kind of thing he or she meant in the previous answer. The list of alternatives given was a = teddy-bear, b = soft animal, c = pillow or blanket, d = doll, e = if something else, what (with a blank space for writing in the answer). The respondents were instructed to choose only one alternative.

The children's depression inventory (CDI) was used to assess the adolescents' depressive symptoms [16]. The CDI is a 27-item self-rated symptom-oriented scale and a suitable depression measurement instrument for children and adolescents from 7 to 17 years of age. The CDI quantifies a range of depressive symptoms, including disturbed mood, hedonistic capacity, vegetative functions, self-evaluation and interpersonal behaviour. Several items concern the consequences of depression in contexts that are specifically relevant to children (e.g. school). Each CDI item consists of three choices, keyed 0, 1 or 2, with higher scores indicating an increasing tendency to depression. For each item, the meaning of each choice can be summarized by the following: 0 = Absence of symptom, 1 = Mild symptom, 2 = Definite symptom. The range of the total score is from 0 to 54. To calculate the total CDI scores in our study we used the mean value of all questions answered for each individual (a range of 0-2). In making comparisons, we used the mean value of that score for each group of adolescents. In addition to the total CDI scores, we used subscales constructed according to the factorization of the CDI scores of the Finnish school-aged population [START_REF] Moilanen | Components of childhood depression[END_REF]: low self-confidence, anhedonia and sadness. Low self-confidence consisted of six items: hating oneself, not being loved by anyone, looking unattractive, being bad, doing everything wrong and doing very badly. Anhedonia consisted of three items: never having fun, being bothered by many things and never having fun at school. Sadness likewise consisted of three items: being sad all the time, feeling like crying and feeling lonely.

It has been shown that the CDI is a reliable and sensitive measure of depressive symptoms in children [START_REF] Brooks | Diagnosis and measurement of adolescent depression: a review of commonly utilized instruments[END_REF], but it is not recommended for use as a sole instrument in screening psychiatric disturbances [START_REF] Kresanov | Validity of child psychiatric screening methods[END_REF]. The CDI is a measure of non-specific psychopathol-ogy rather than of pure depression [START_REF] Aronen | Childhood depressive symptoms predict psychiatric problems in young adults[END_REF]. The validity of the CDI in screening depressive symptoms among children and adolescents has also been demonstrated in Finnish studies [START_REF] Kumpulainen | The persistence of psychiatric deviance from the age of 8 to the age of 15 years[END_REF].

j Data analyses

The data were analysed using the Statistical Package of Social Sciences 13.0 and 16 (SPSS 13.0 and 16).

First, the whole study group was divided into those who did not possess a transitional object (non-TO-users) and those who did (TO-users). Girls and boys were then separately divided into TO-users and non-TO-users. Further analyses compared non-TO-users to TO-users in the group as a whole and for each gender separately. The categorical variables were analysed with cross-tabulations and Pearson's chi-square test. The differences between the mean values of the CDI total scores and its subscales by TO use and gender were analysed with an independent sample t test and controlled with a nonparametric test (Mann-Whitney U test).

Results j Prevalence of TO use

Out of the whole study group, 28.7% (n = 285) had some kind of TO at bedtime or when away from home or traveling. The figure for girls was 37% (n = 208) compared to only 18% (n = 77) for boys (Table 1). The gender difference was significant (P < 0.001).

Of all those having a TO, 62% (n = 176) listed a teddy-bear or other soft animal as their TO. A total of 12% (n = 36) of all the students who had any TO named a pillow or blanket and only 0.7% (n = 2) a doll. A group of 22% (n = 62) answered that their TOs were some other item than those named in the questionnaire (for instance a book or a pen). A total of 72% of girls with a TO had a teddy-bear or other soft animal as a TO, while 49% of boys with a TO used other things, such as books, pens or toys. The gender differences were statistically significant. More details are shown in Table 2.

j Depressive symptoms and TO use

There was no gender difference in the CDI total scores; boys and girls did not differ in the stage of symptomatology in depression (mean 0.34, SD 0.22 and mean 0.33, SD 0.28, respectively).

In the subscales boys showed more significant anhedonia than girls (P = 0.000), while girls had significantly lower self-confidence than boys (P = 0.004). With regard to sadness there was no difference between boys and girls.

In the group of TO-users the mean of the total CDI scores was 0.36 (SD 0.27), while in the group of nonusers it was 0.33 (SD 0.24). There was a non-significant trend (P = 0.053) in CDI total scores between TO-users and non-users. With regard to the CDI subscales, TO-users showed markedly more sadness than the non-users (P = 0.001) (TO-users mean 0.20, SD 0.32; non-users 0.12, SD 0.26). Anhedonia and low self-confidence were not related to TO use.

TO-using girls had a higher CDI total score than non-TO-using ones. There was a non-significant trend (P = 0.08).

In the group of TO-using girls, sadness was markedly common compared to non-TO-using girls (P = 0.002). Low self-confidence and anhedonia were not connected to TO use in girls. TO-using boys had higher means in the total CDI score, in anhedonia and in sadness than non-TO-using boys, but the differences were not statistically significant. The results are presented in Table 3.

Discussion

It has been suggested that more research is needed concerning the use of TO after childhood, because of its possible role as a visible representation and marker of mental distress [START_REF] Arthern | How do transitional objects work? The client's view[END_REF][START_REF] Bacchar | Childhood vs. adolescence transitional object attachment, and its relation to mental health and parental bonding[END_REF]. There have been only few studies exploring the use of TOs in stressful situations in adolescence, or the general occurrence of TOs at that age. In our study the use of a TO in adolescence was common, especially among girls. The prevalence of TO use in the normal adolescent population was higher than that found by Bacchar et al. [START_REF] Bacchar | Childhood vs. adolescence transitional object attachment, and its relation to mental health and parental bonding[END_REF]: 27% compared to their 22%. This may be due to the younger age of our group, 14.5 versus 16.7. The higher TO use among girls than among boys, and the use of soft toys in particular, may reflect the emotional life of girls at the age of 14.

Our study does not totally confirm the results of the study by Markt and Johnson [START_REF] Markt | Transitional objects, pre-sleep rituals, and psychopathology[END_REF], who found a strong connection between TO use and depression in college-age students: the indications we found were similar but weaker. We did find some connections between depressive symptoms and TO use: sadness, among girls in particular, showed a clear connection. Developmental regression in youth is a common phenomenon and a transitional period before autonomy. Adolescents who are in developmental regression and feel sad may practice a similar TO use as in childhood. The use of a TO may work in the same way as in childhood, as a defence against anxiety, especially of separation and depressive types.

The mean scores of depressive symptoms in our study did not differ by gender. This is similar to previous studies [START_REF] Kumpulainen | The persistence of psychiatric deviance from the age of 8 to the age of 15 years[END_REF][START_REF] Moilanen | Components of childhood depression[END_REF][START_REF] Samm | Children's depression inventory in Estonia: single items and factor structure by age and gender[END_REF]. In general, the boys in our study reported more symptoms of anhedonia and girls of low self-confidence. With regard to boys' anhedonia this result is consistent with the results of an earlier Finnish study [START_REF] Moilanen | Components of childhood depression[END_REF]. In our study girls had lower self-confidence than boys. The psychiatric symptomatology of boys is mostly extroverted, while among girls it is of a more introverted and emotional type. The inability to gain pleasure from enjoyable experiences may make the boys behave idly and react extrovertedly to obtain some response. Previous studies of self-image in girls have also shown a higher correlation with depressive symptoms than in boys [START_REF] Erkolahti | Self-image and depressive symptoms among adolescents in a nonclinical sample[END_REF].

j Limitations

One of the limitations of our study was the rather large number of students absent from school on the day of the study. Because of the rule of anonymity it was not possible to re-test those who had been absent. The number of excluded students was also rather large; these groups may have included students with more problems than those included. Another limitation which may weaken our study is the larger number of girls participating. Our final sample was nevertheless large in both genders and represented the whole city, with children from all social classes.

j Practical meaning of the study of TO use in adolescence

Although prolonged attachment to a TO is not as such an indication of psychopathology, it may denote a vulnerability to adolescent perturbation and difficulty in coping with the emotionally laden developmental process of the transition from childhood to adolescence and adulthood. The presence of a TO in fact offers new possibilities for therapeutic applications in confronting adolescents with mild or moderate developmental and psychological problems. Winnicott [START_REF] Winnicott | Playing and reality[END_REF][START_REF] Winnicott | The maturational processes and the facilitating environment[END_REF][START_REF] Winnicott | The location of cultural experiences[END_REF] and Roland [START_REF] Roland | Imagery and symbolic expression in dreams and art[END_REF] suggest that the psychological meanings of TO use in childhood are closely allied with imagination, playfulness, creativity, art and religion in later years and over the whole lifetime. Child therapy has a long tradition of using play, imagination and creativity in working with children [START_REF] Jernberg | Theraplay. Jossey-Bass[END_REF]. Dockar-Drysdale [START_REF] Dockar-Drysdale | The provision of primary experience: Winnicottian work with children and adolescents[END_REF] describes work in a therapeutic unit for severely emotional disturbed teenage boys, where the therapists and other staff members use TOs as part of caring. ''Teddy-bear groups'' were started for boys who were too avoidant to speak or communicate with the therapist, other staff members or the other boys. Communicating first through teddy-bears helped these avoidant boys to join the group and to gradually start to speak as themselves and about themselves. The therapists also use TOs as part of the therapy process in the boys' individual therapy. Taking care of one's TO together with the therapists, the boy is able to experience true comfort, caring and maintaining [START_REF] Dockar-Drysdale | The provision of primary experience: Winnicottian work with children and adolescents[END_REF]. It is important to explore the use of TOs as an element in adolescent therapy. Perhaps a TO could be a supporting element not only in adolescent therapy but also in daily life; no longer as merely a plaything, but as an object offering a possibility of symbolic function which has not yet been developed. The connection found in our study between girls' sadness and TO use was very clear. Because of the sparse literature on this subject and the pioneering nature of this work, further comparisons to earlier studies cannot be drawn. Further work is needed for a clear understanding of the role of TOs in the world of adolescents.

Table 1

 1 The prevalence of TO use in adolescents by gender (N = 992)

	TO use	Boys (n = 433)		Girls (n = 559)		Total (N = 992)
		%	n	%	n	%	n
	Uses a TO	17.8	77	37.2	208 ***	28.7	285
	Does not use a TO	82.2	356	62.8	351	71.3	707
	The differences between boys and girls in TO-using was investigated by Pearson's chi-square test
	* P £ 0.05, ** 0.001 < P £ 0.01, *** P £ 0.001

Table 2

 2 Articles named as having role of TO by adolescents using one (N = 285)

	TO named	Boys (N = 77)		Girls (N = 208)		Total (N = 285)
		%	n	%	n	%	n
	Teddy-bear or other soft animal	35.1	27	71.7	149 ***	61.8	176
	Blanket or pillow	13.0	10	12.5	26	12.6	6
	Doll Other (book, pen, toy etc.)	0 49.4	0 38	1.0 11.5	2 24 ***	0.7 21.8	2 62
	Not specified	2.6	2	3.4	7	3.2	9

Significance of differences between genders in naming TO tested by Pearson's chi-square test * P £ 0.05, ** 0.001 < P £ 0.01, *** P £ 0.001

Table 3

 3 Mean (M) values and standard (SD) deviations for total CDI scores (range 0-2) and CDI subscales by gender in whole study group, non-TO using groups and TO-using groups CDI, the children depression inventory; low self confidence, subscale of CDI; anhedony, subscale of CDI; sadness, subscale of CDI Significance of differences in means between groups tested by T test and controlled by non-parametric Mann-Whitney U test * P £ 0.05, ** 0.001 < P £ 0.01, *** P £ 0.001

	Study group	Total CDI	Low self confidence	Anhedony	Sadness
		M (SD)	M (SD)	M (SD)	M (SD)
	The whole study group N = 992	0.34 (0.25)	0.32 (0.32)	0.45 (0.37)	0.14 (0.28)
	Boys n = 433 (43.6%)	0.34 (0.28)	0.29 (0.33)	0.51 (0.39)	0.13 (0.27)
	Girls n = 559 (56.4%)	0.33 (0.22) P = 0.67	0.35 (0.30) P = 0.004 **	0.41 (0.36) P = 0.000 ***	0.16 (0.29) P = 0.062
	Non-TO-users n = 707 (71.3%)	0.33 (0.24)	0.31 (0.30)	0.46 (0.41)	0.12 (0.26)
	TO-users n = 285 (28.7%)	0.36 (0.27) P = 0.053	0.34 (0.33 P = 0.25	0.45 (0.36) P = 0.90	0.20 (0.32) P = 0.001 ***
	Non-TO-using boys n = 356 (82.2%)	0.33 (0.27)	0.29 (0.32)	0.50 (0.48)	0.12 (0.26)
	TO-using boys n = 77 (17.8%)	0.38 (0.34)	0.29 (0.38)	0.58 (0.37)	0.18 (0.35)
		P = 0.19	P = 0.90	P = 0.16	P = 0.14
	Non-TO-using girls n = 351 (62.8%)	0.32 (0.21)	0.34 (0.30)	0.41 (0.37)	0.13 (0.26)
	TO-using girls n = 208 (37.2%)	0.36 (0.23) P = 0.08	0.36 (0.29) P = 0.40	0.41 (0.35) P = 0.91	0.21 (0.32) P = 0.002 **

Transitional object in adolescence

R. Erkolahti and M. Nystro ¨m


MD, PhD (& Celso Arango
email: carango@mce.hggm.es

PhD Olalla Robles

MD, PhD Mara Parellada

PhD David Fraguas

MD Ana Ruiz-Sancho

MD Oscar Medina

PhD Arantzazu Zabala

Igor Bombín

PhD Dolores Moreno

PhD Igor Bombı ´n

PhD Ae O Robles

MD Ae O Medina

MD Ae D Moreno

Olanzapine compared to quetiapine in adolescents with a first psychotic episode

Keywords:

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

There has been a drastic increase in the prescription of antipsychotics in children and adolescents in recent years [START_REF] Olfson | National trends in the outpatient treatment of children and adolescents with antipsychotic drugs[END_REF]. Nevertheless, there is very limited efficacy or safety evidence from randomized controlled trials to support these prescribing trends in children and adolescents with psychotic symptoms [START_REF] Correll | Recognizing and monitoring adverse events of secondgeneration antipsychotics in children and adolescents[END_REF]. In fact, there have been more studies with SGA for the treatment of disruptive behaviors and developmental disorders than in patients with psychotic symptoms [START_REF] Findling | Update on the treatment of bipolar disorder in children and adolescents[END_REF]. To our knowledge, only three doubleblind studies have compared the efficacy of different antipsychotics. Moreover, two of these studies were performed with a very low prevalence entity: treatment resistant patients with childhood-onset schizophrenia [START_REF] Kumra | Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison[END_REF][START_REF] Shaw | Childhood-onset schizophrenia: a double-blind, randomized clozapineolanzapine comparison[END_REF]. Kumra et al. [START_REF] Kumra | Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison[END_REF] found that clozapine was superior to haloperidol in the treatment of 21 treatment resistant patients with prepubertalonset schizophrenia. In a more recent study, clozapine was significantly superior to olanzapine only for the treatment of negative symptoms [START_REF] Shaw | Childhood-onset schizophrenia: a double-blind, randomized clozapineolanzapine comparison[END_REF]. In the only other double-blind randomized study, Sikich et al. [START_REF] Sikich | A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial[END_REF] studied 50 patients with psychotic symptoms, with a mean length of illness of 2.4 years. Haloperidol, olanzapine, and risperidone showed similar efficacy in symptom reduction. In this study, weight gain and extrapyramidal effects appeared more prevalent and severe than reported in adults. Most studies are short term, usually lasting 6-8 weeks [START_REF] Shaw | Childhood-onset schizophrenia: a double-blind, randomized clozapineolanzapine comparison[END_REF][START_REF] Sikich | A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial[END_REF]. We are not aware of any previous randomized controlled trial with two SGAs in first episode psychosis in adolescence.

This study was designed to provide prospective, randomized information at 6 months about the efficacy and safety of two-second generation antipsychotics widely prescribed in pediatric populations. Based on previous studies in adult first episode psychosis and studies on tolerability in pediatric populations, we hypothesized that there would not be a difference between quetiapine and olanzapine in terms of symptom reduction, and that side effects would be very prevalent in this population and different for the two antipsychotics.

Methods j Study design

This is a 6-month, comparative, randomized (quetiapine vs. olanzapine), open label, parallel group study in adolescent patients with first episode psychosis. In this article, we report on clinical efficacy, tolerability, and safety of antipsychotic drug treatment. However, the primary outcome for this trial was cognitive efficacy. Results for cognitive outcome are reported elsewhere (Robles et al., submitted). Therefore, here we focus on the clinical secondary variables.

j Subjects

Fifty patients consecutively admitted to the Adolescent Unit of Hospital General Universitario ''Gregorio Maran ˜o ´n'' (Madrid, Spain) with a diagnosis of psychosis (i.e., schizophrenia or any other psychotic disorder according to DSM-IV criteria) were invited to participate in the study. All patients had a first episode of psychosis before the age of 18, lasting less than 1 year after onset of the first positive symptom (mean duration of delusions 0.3 ± 0.3 years; hallucinations 0.4 ± 0.5 years). Adolescents were 12-18 years of age.

Diagnostic information was collected at baseline by means of the Kiddie-SADS-Present and Lifetime Version (K-SADS-PL). A clinical psychiatrist with formal training in the K-SADS-PL interviewed participants and administered diagnostic, psychiatric, safety, and tolerability scales over the six research visits (see ''Outcome measures'' for scales and frequency). The Internal Review Board (IRB) approved all procedures, including recruitment and consent. Written informed consent was obtained from participants and their parents or legal guardians prior to enrollment in the study.

We excluded subjects if the psychotic symptoms appeared to result from acute intoxication or withdrawal (if psychotic symptoms did not persist after 14 days of a negative urine drug screening), if they met DSM-IV criteria for any substance abuse, mental retardation, or pervasive developmental disorder, suffered from any organic central nervous system disorder, had a history of traumatic brain injury with loss of consciousness, were pregnant or breast-feeding, or were taking olanzapine or quetiapine before enrolment. Use of other antipsychotic drugs other than olanzapine or quetiapine before enrolment was allowed.

Patients were diagnosed again at 6 months by the patient's attending psychiatrist, according to DSM-IV criteria. The final sample included 17 patients with schizophrenia, 13 patients with bipolar disorder, and 20 patients with ''other'' psychotic disorders. Specific diagnoses at 6 months for patients included in the two treatment arms are provided in Table 1. Figure 1 provides a detailed explanation of the flow of participants throughout the trial.

j Randomization

Adolescents were randomized to one of two treatment groups (quetiapine or olanzapine). Stratified random sampling was conducted according to two participant characteristics: age and gender.

j Medication

Four patients randomized to quetiapine and eight patients randomized to olanzapine had previously received antipsychotics (16.7% of the quetiapine group and 30.8% of the olanzapine group). All patients were prescribed risperidone 2-6 mg (flexible dose at the discretion of the clinician), between 3 and 5 days prior to randomization. For patients that were not on antipsychotic treatment before, we needed between 3 and 5 days to have the informed consent explained to patients and legal representatives and have it signed. The IRB from our hospital did not allow having patients off medication before randomization. 25 patients were antipsychotic naı ¨ve prior to inclusion in the study (quetiapine: n = 15; olanzapine: n = 10). In addition we thought that the use of the same antipsychotic before randomization would reduce the heterogeneity of carrying over effects from previous different antipsychotics. Antipsychotics, other than the study drugs, were not permitted throughout the clinical trial.

Adolescents were randomized to one of two treatment groups: quetiapine (n = 24) or olanzapine (n = 26). The dose administered was determined at the discretion of the clinician. Adjunctive medications other than different antipsychotics were allowed during the clinical trial. j Outcome measures

Efficacy measures

Clinical evaluations were performed by one of the four adolescent psychiatrists participating in the research study. The primary outcome measure for symptom reduction was the Positive and Negative Symptoms Scale (PANSS) [START_REF] Kay | The positive and negative syndrome scale (PANSS): rationale and standardisation[END_REF] Secondary clinical outcome measures were: the Global Assessment Scale for Children (C-GAS) [START_REF] Shaffer | A children's global assessment scale (CGAS)[END_REF], Clinical Global Impression-Severity score (CGI-S) [START_REF] Guy | Clinical Global Impression[END_REF], Hamilton Depression Rating Scale (HDRS-21) [15], and the Young Rating Mania Scale (YRMS) [START_REF] Young | A rating scale for mania: reliability, validity and sensitivity[END_REF]. The strengths and difficulties questionnaire (SDQ) [START_REF] Goodman | The extended version of the strengths and difficulties questionnaire as a guide to child psychiatric caseness and consequent burden[END_REF][START_REF] Goodman | The strengths and difficulties questionnaire: a research note[END_REF] for children and adolescents was also administered. This pediatric scales provide not NOS not otherwise specified a No significant differences were observed between the two treatment groups (Mann-Whitney U; P > 0.05) b No significant differences were observed between the two treatment groups (Chi-square; P > 0.05) c Significant differences were observed between the two treatment groups (Chi-square; P < 0.05) d Not applicable when using the Mann-Whitney U test e Percentage calculated according to the total randomized sample (quetiapine n = 24, olanzapine n = 26)

only third party and self-rated information (it has a parent, teacher and self-rated versions), but also provide important information in addition to psychopathology (behavioral, emotional, and social). All scales were administered at baseline, visit 1 (day 7), visit 2 (day 15), visit 3 (day 30), visit 4 (day 90), and visit 5 (day 180), except for the SDQ scale (in its three versions), which was administered only at baseline and end of study. All scales were administered by four board-certified psychiatrists with clinical experience with children and adolescents. Intraclass correlation coefficients for the four psychiatrists ranged from 0.72 to 0.96 for the total and PANSS positive, negative, and general psychopathology subscores.

Measures of safety and tolerability

Primary outcome measures for safety and tolerability were: weight changes (measured as increase in kilograms and body mass index (BMI)), UKU scale of adverse reactions [START_REF] Lingjaerde | The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients[END_REF], Barnes Akathisia Scale [START_REF] Barnes | The Barnes Akathisia rating scale-revisited[END_REF], and Simpson Neurological Rating Scale for extrapyramidal side effects [START_REF] Simpson | A rating scale for extrapyramidal side effects[END_REF]. All safety and tolerability scales were administered visit-wise. Blood cell counts, electrolytes, renal function, liver function, energy metabolism (glucose, HgbA1c, lipid profile), prolactin, and EKG were performed at baseline and at each visit. All blood tests were performed in a fasting state.

j Data analysis/statistical methods Descriptive statistics were obtained on demographic and outcome variables, using means with standard deviations for continuous variables and frequency distributions for categorical variables. Differences in qualitatively measures between groups were compared by means of Chi-square. Efficacy, safety, and tolerability measures were assessed using the Mann-Whitney U nonparametric test to compare quetiapine versus olanzapine at baseline and 6 months, and the Wilcoxon nonparametric test to examine changes between baseline and 6 months within treatment arms. An intent-to-treat efficacy analysis was performed for all patients who fulfilled the inclusion criteria, with the last observation carried forward (LOCF) for any patient not completing the study.

Cases in which no data was obtained after baseline were eliminated. All statistical tests were two tailed; alpha (level of significance) was 5%. The SPSS 12.0.1 statistical package was used for all analyses.

Results j Subjects

Demographic variables for subjects participating in the study are presented in Table 1. The treatment groups were comparable in age, gender, time elapsed since onset of the first psychotic symptom, parental education, and family socioeconomic status. There was a higher proportion of Hispanic patients in the olanzapine group (Chi-square; P < 0.05). With respect to baseline symptomatology, adolescents in the olanzapine group scored worse on the general psychopathology scale (U = 179.00, P = 0.027) and total score (U = 162.00, The HDRS-21, YMRS, and CGI-S scores were all significantly decreased in both treatment groups. The C-GAS scores also significantly improved in the two treatment groups (Table 4).

The SDQ patient subscore was significantly decreased in patients treated with olanzapine (W = )2.675, P = 0.007), but not in those treated with quetiapine (W = )0.534, P = 0.593). The other SDQ subscales (parent and teacher subscores) were significantly decreased in both treatment groups (Table 4).

Comparison of treatment groups

Between-group comparisons of improvement on all the symptomatic scales failed to detect statistical differences (Table 4) with the exception of the SDQ subscale for patients (U = 122.500, P = 0.026) in favor of olanzapine.

j Safety measures

Spontaneous adverse events (i.e. other side effects than assessed by means of UKU) were reported for nine patients in the study: six patients on quetiapine and three patients on olanzapine. Only one of the reported adverse events was considered serious: physical aggression towards others, committed by a patient on quetiapine. The adverse event was considered unrelated to medication. Three patients experienced adverse events considered of moderate intensity: polyarthritis (patient on quetiapine), wrist fracture (patient on olanzapine), and muscle contracture (patient on quetiapine). All other adverse events were mild in intensity. None of the drop-outs from the study were due to an adverse event.

Change from baseline within treatment groups

Table 5 shows data on subjective side effect symptoms, as measured with the UKU, that were present at least in a 20% of patients at any time during the study with either of the two drugs. Significant weight gain was observed in both groups (olanzapine: 15.5 kg, W = )3.621, P < 0.001; quetiapine: 5.4 kg, W = )2.899, P = 0.004). Weight gain was disproportionate to increase in height, with BMI increases also significant for both groups (olanzapine baseline 21.7, end of study 27.1, W = )3.181, P = 0.001; quetiapine baseline 21.5, end of study 23.3, W = )2.919, P = 0.004).

The effect of each treatment on various safety parameters is summarized in Table 5.

There were no significant within-group changes with either of the two antipsychotics in systolic or diastolic blood pressure, heart rate, or QTc. There were no differences in electrolytes, liver function, renal function, energy metabolism (glucose, HgbA1c, lipid profile), or hemogram (hematite, hematocrit) parameters in either of the two groups. With respect to cholesterol levels, an increase was observed in HDL for the quetiapine group (W = )2.670, P = 0.008), and an increase in total cholesterol for both quetiapine (W = )2.638, P = 0.008) and olanzapine (W = )2.379, P = 0.017). A decrease in the thyroid hormone T4 was observed for the quetiapine group

Comparison of treatment groups

There were no significant between-group differences in the changes in prevalence of UKU items with the exception of rigidity (Mann-Whitney, P < 0.05). Rigidity was more frequently present in patients treated with olanzapine.

Patients on olanzapine gained more weight (U = 34.500, P < 0.001) and had a greater increase in BMI (U = 49.000, P = 0.015) than patients treated with quetiapine (Table 5; Fig. 4).

There were no between-group differences in any of the cardiac, liver function, renal function, energy metabolism (glucose, HgbA1c, lipid profile), hemogram, or thyroid parameters. The HDL increase was more prominent in patients on quetiapine than in patients on olanzapine (U = 31.000, P = 0.019).

Discussion

Adolescent patients treated with both olanzapine and quetiapine had a reduction in symptomatology over a 6-month period. The drugs had different side effect profiles. No significant differences were observed between the two treatment arms at the 6-month evaluation in terms of clinical reduction in symptoms, with patients in both arms experiencing significant clinical improvements, with the exception in one of the SDQ scores. Patients receiving olanzapine rated themselves as having improved more in terms of behaviour than patients receiving quetiapine. This difference was not supported by the parent and teacher versions of the scale, which showed significant improvements with either of the two antipsychotics. This result is in line with some previous studies reporting a better subjective feeling with olanzapine than with other second generation antipsychotics such as clozapine or risperidone [START_REF] Lieberman | Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol[END_REF][START_REF] Naber | Improvement of schizophrenic patients' subjective well-being under atypical antipsychotic drugs[END_REF], although results are controversial (see, among others, [START_REF] Keefe | Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison[END_REF][START_REF] Velligan | Does cognitive function improve with quetiapine in comparison to haloperidol?[END_REF][START_REF] Voruganti | Cognition, functioning and quality of life in schizophrenia treatment: results of a one-year randomized controlled trial of olanzapine and quetiapine[END_REF]), and this result could also well manifest a Type I error. To our knowledge, no formal comparative studies have been carried out on subjective feelings of adolescents taking antipsychotics, and this is an area that definitely needs more research, as subjective feelings have been related to medication compliance, quality of life, and functional outcome [START_REF] Charach | A theoretical approach to medication adherence for children and youth with psychiatric disorders[END_REF][START_REF] Naber | Subjective well-being under the neuroleptic treatment and its relevance for compliance[END_REF][START_REF] Naber | Improvement of schizophrenic patients' subjective well-being under atypical antipsychotic drugs[END_REF].

Both groups showed significant reduction in both total psychopathology and positive symptoms. However, a reduction in negative symptoms was observed only for patients on quetiapine, whereas a reduction in general psychopathology was significant only for those patients on olanzapine. Given the lack of differences in the different symptom domains between different antipsychotics in previous studies with much larger samples (CATIE [START_REF] Lieberman | Effectiveness of antipsychotic drugs in patients with chronic schizophrenia[END_REF], EUFEST [START_REF] Kahn | Effectiveness of antipsychotic drugs in firstepisode schizophrenia and schizophreniform disorder: an open randomised clinical trial[END_REF], CUtLASS [START_REF] Jones | Randomized controlled trial of the effect on quality of life of second-vs first-generation antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1)[END_REF]), these findings may be more likely constitute a Type II error due to small sample size than a true difference reflecting a different pharmacological profile for the two drugs.

Results are comparable to previous reports showing efficacy of SGAs in pediatric populations with psychotic symptoms. In a previous 8-week doubleblind, randomized, controlled trial in 50 children and adolescents with psychotic symptoms, comparing risperidone, olanzapine, and haloperidol, there was no difference in efficacy among the drugs, with all three antipsychotics providing a significant reduction in psychotic symptoms [START_REF] Sikich | A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial[END_REF]. More recently, a 12-week open-label, randomized study comparing risperidone and olanzapine efficacy in 25 child-onset schizophrenia patients reported that both drugs provided a similar significant reduction in psychotic symptoms [START_REF] Mozes | An Open-label randomized comparsion of olanzapine versus risperidone in the treatment of childhood-onset schizophrenia[END_REF]. In an 8-week open label study in 16 adolescent patients with schizophrenia, schizophreniform, or schizoaffective disorders, olanzapine significantly decreased PANSS scores [START_REF] Findling | A prospective, openlabel trial of olanzapine in adolescents with schizophrenia[END_REF]. Further studies are needed to elucidate whether different antipsychotics have distinct efficacy profiles for different symptom domains, and more especially, different safety and side effect profile.

It is noteworthy that a high prevalence of side effects was found in this adolescent sample. Despite the lack of significant differences between the two treatments with respect to the presence of side effects as measured by the UKU (with the exception of rigidity and diminished sexual desire), there were many other symptoms present in more than 20% of patients Only those with at least 20% prevalence at some point during the study are shown in the table a Mann-Whitney U test for independent samples; significant differences when P < 0.05 b Wilcoxon test for non-independent samples; significant differences when P < 0.05 throughout the study. More than 70% of patients in both groups experienced somnolence at some point during the study and, more importantly, 69% of patients on quetiapine and 71% of patients on olanzapine experienced somnolence after 6 months of treatment. In addition, 37% of patients on quetiapine and 56% of patients on olanzapine experienced lack of concentration. These are symptoms with important daily living implications in school-age patients that should be taken in consideration when prescribing antipsychotics [START_REF] Arango | Clinical effectiveness of new generation antipsychotics in adolescent patients[END_REF]. Clearly, more data on safety and tolerability of antipsychotics is needed in this population.

Most of the patients in this study experienced substantial weight gain. These data are clinically important for many reasons. A weight gain greater than 15 kg in 6 months changes the body's physical appearance at an age of great emotional turmoil. This may be specifically important in terms of treatment adherence in adolescents who worry with their physical appearance [START_REF] Arango | Clinical effectiveness of new generation antipsychotics in adolescent patients[END_REF]. We did not find any differences between the two drugs in terms of drug discontinuation, but this could be due to the short follow-up or the clinical trial setting. Also noteworthy is the increased risk of chronic health problems associated with obesity such as diabetes, hypertension, and cardiovascular morbidity. These increases in weight are similar to those reported in first episode studies in adults on quetiapine [START_REF] Fraguas | Metabolic and hormonal side effects in children and adolescents treated with second-generation antipsychotics[END_REF][START_REF] Kopala | Treatment of a first episode of psychotic illness with quetiapine: an analysis of 2 year outcomes[END_REF]. For olanzapine, we have been able to locate only studies assessing adult first episode patients for 12 weeks with 6-7.3 kg weight gain [START_REF] Lieberman | Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol[END_REF][START_REF] Sengupta | Weight gain and lipid metabolic abnormalities induced by olanzapine in first-episode, drug-naive patients with psychotic disorders[END_REF], and up to 4 months with 7.7 kg weight gain [START_REF] Sengupta | Weight gain and lipid metabolic abnormalities induced by olanzapine in first-episode, drug-naive patients with psychotic disorders[END_REF]. Weight gain and metabolic changes have been described in this population [START_REF] Correll | Pharmacogenetics of antipsychotic-induced weight gain[END_REF][START_REF] Correll | Recognizing and monitoring adverse events of secondgeneration antipsychotics in children and adolescents[END_REF]. However, the weight gain in the present study is greater than that seen in more chronic pediatric patients [START_REF] Findling | A prospective, openlabel trial of olanzapine in adolescents with schizophrenia[END_REF][START_REF] Mozes | Clozapine treatment in very early onset schizophrenia[END_REF][START_REF] Shaw | Childhood-onset schizophrenia: a double-blind, randomized clozapineolanzapine comparison[END_REF][START_REF] Sikich | A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial[END_REF] that may have already gained weight due to antipsychotic treatment prior to study entry. Therefore, first episode psychosis patients may be a population at greater risk for this side effect, regardless of the age. This study also points to the need to assess weight gain in studies with longer follow-up periods, as this side effect does not seem to plateau after the first 6 months of treatment. Weight should be routinely measured quantitatively, since scales such as the UKU that measures only if weight gain is present or absent, miss significant differences between drugs that are clinically meaningful, as was the case in this study (Table 5).

Our results relative to free-thyroid hormone (FT4) reduction are in the line with previous reports in adult [START_REF] Conley | Secondgeneration antipsychotics for schizophrenia: a review of clinical pharmacology and medication-associated side effects[END_REF] and adolescent populations [START_REF] Fraguas | Metabolic and hormonal side effects in children and adolescents treated with second-generation antipsychotics[END_REF][START_REF] Mcconville | Longterm safety, tolerability, and clinical efficacy of quetiapine in adolescents: an open-label extension trial[END_REF][START_REF] Mcconville | Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders[END_REF][START_REF] Shaw | A study of quetiapine: efficacy and tolerability in psychotic adolescents[END_REF] using similar antipsychotic doses and treatment times. Treatment with quetiapine was related to a significant decrease in FT4. Kelly and Conley argue that this effect may be secondary to competitive metabolism of thy-roid hormones and quetiapine by UDP-glucuronosyltransferase [START_REF] Mcconville | Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders[END_REF]. In our study, FT4 levels were within normal limits both at baseline and the 6-month assessment. Therefore, such a decrease did not have clinical implications. Further studies are needed to evaluate FT4 changes with long-term treatment.

We also found that total cholesterol levels increased significantly in patients receiving olanzapine and quetiapine. HDL cholesterol increased only in the group treated with quetiapine. Thus, the increase in total cholesterol in patients treated with olanzapine seems to be driven by a non-significant increase in LDL cholesterol. Olanzapine was reported to be related to an increase in total cholesterol in a study in five adolescents [START_REF] Gothelf | Olanzapine, risperidone and haloperidol in the treatment of adolescent patients with schizophrenia[END_REF], although findings on the effects of olanzapine, risperidone, and quetiapine on cholesterol levels among adolescents are not conclusive [START_REF] Fedorowicz | Metabolic side effects of atypical antipsychotics in children: a literature review[END_REF][START_REF] Fraguas | Metabolic and hormonal side effects in children and adolescents treated with second-generation antipsychotics[END_REF][START_REF] Kopala | Treatment of a first episode of psychotic illness with quetiapine: an analysis of 2 year outcomes[END_REF][START_REF] Sikich | A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial[END_REF].

Regarding concomitant medications, patients on olanzapine experienced dystonia and required anticholinergics in a higher proportion than patients on quetiapine, although this difference was not significant. This may indicate a higher susceptibility to extrapyramidal symptoms with olanzapine as compared to quetiapine in this population. In a previous study on SGA tolerability in a pediatric population, we reported that patients treated mostly with SGAs over a one-year showed more dyskinetic movements than patients treated for less than 1 month [START_REF] Laita | Antipsychotic-related abnormal involuntary movements and metabolic and endocrine side effects in children and adolescents[END_REF]. Maturation of the dopamine system during childhood and adolescence may affect susceptibility to motor side effects differently, depending on age. Therefore, subgroups should be stratified by age when assessing dopamine-related side effects in young people exposed to SGAs.

There are several methodological limitations to this study. Firstly, we used an open-label instead of a double-blind design, which can change the expectations of patients and their caregivers, as well as therapists, even when medication is assigned randomly, thus influencing the outcome of treatment. Secondly, the small sample size of our groups may limit the study's ability to detect moderate to small differences between treatments that may be clinically significant (Type II error). In addition, it makes it difficult to do any sort of subgroup analyses, for instance between different diagnoses or age subgroups. Thirdly, a variety of concomitant medications was used. Although there were no significant differences between any particular class of adjunctive medication used in the two groups, it is theoretically possible that both the efficacy and side effects observed in this study were due to or modulated by the adjunctive medication rather than the antipsychotic drug. Fourthly, although similar completion rates were observed for both the quetiapine sample (66.7%) and the olanzapine sample (61.5%), we observed high dropout rates in both treatment arms, which may limit the generalizability of our results. However, the literature reveals 6-month studies with higher attrition rates. In a study comparing quetiapine 300, 600 mg, and haloperidol, drop-out rates increased to 58, 50, and 35%, respectively, before week 24 [START_REF] Velligan | Does cognitive function improve with quetiapine in comparison to haloperidol?[END_REF]. Furthermore, in another 6-month study, only 44% of the entire sample (total n = 12) completed the entire protocol [START_REF] Purdon | Selective serotonin reuptake inhibitor modulation of clozapine effects on cognition in schizophrenia[END_REF]. Finally, we used a heterogeneous sample of diagnoses. Differential diagnosis of psychotic disorders is very difficult in a pediatric population due to the atypicality and non-specificity of symptoms in psychotic episodes at this age (e.g., noncongruent delusions or hallucinations in a first episode bipolar patient) and the lack of longitudinal information about the disease course. In addition, antipsychotics have no proven disease specific efficacy or safety profile and are commonly used in all the diagnoses included in this sample. The heterogeneity of this sample should be taken into account when assessing the generalizability of the study. Diagnostic differences may also influence the use of or the response to concomitant medications.

In summary, patients in both treatment groups had a significant reduction in most clinical measurements. Side effects were common with the two drugs. The increase in weight experienced by patients treated with olanzapine during the 6 months of the study does not seem to be counterbalanced by better efficacy and, therefore, olanzapine should not be a first choice drug for this population.

Fig. 3 Fig. 2

 32 Fig. 3 PANSS positive subscale scores over time by treatment group

Fig. 4

 4 Fig. 4 Change in weight over time by treatment group

j

  Acknowledgments This work was supported by Supported by Investigator Initiated Study (D1441C00007) funded by AstraZeneca,, Fundacio ´n Alicia Koplowitz, and Instituto de Salud Carlos III, Centro de Investigacio ´n Biome ´dica en Red de Salud Mental, CI-BERSAM.

Table 1

 1 Socio-demographic and clinical characteristics

	Variables	Quetiapine			Olanzapine			Analysis
		n	Mean	SD	n	Mean	SD	Statistic	df d	P
	Age (years) a Parental years of education a	24 21	16.3 10.6	1.1 3.5	26 15	15.7 9.4	1.4 3.8	U U	--	0.132 0.736
				n	% e	n	% e	Statistic	df	P
	Gender b							v 2	1	0.848
	Male			19	79.2	20	76
	Female Race or ethnic group c			5	20.8	6	24	v 2	3	0.030
	Caucasian			21	87.5	20	76.9
	Caribbean Black			2	8.3	0	0
	Hispanic			0	0.0	6	23.1
	Gipsy Parental socioeconomic status (Hollingshead Redlich) b	1 8	4.2 100.0	0 9	0 100	v 2	2	0.667
	I			0	0.0	0	0
	II			0	0.0	0	0
	III			2	25.0	4	44.4
	IV			3	37.5	2	22.2
	V			3	37.5	3	33.3
			n	% e		n	% e	Statistic	df	P
	DSM-IV diagnosis b							v 2	2	0.425
	Schizophrenia		8	33.3	9	34.6
	Bipolar disorder		8	33.3	5	19.2
	Other psychoses		8	33.3	12	46.2
	Psychosis NOS		2	25		4	33.3
	Schizoaffective disorder		2	2 5		3	2 5
	Schizophreniform disorder		2	25		2	16.6
	Major depressive episode with psychotic features	2	2 5		3	2 5

Table 2 .

 2 Subject flowchart P = 0.010) of the PANSS. No differences were observed for the positive (U = 245.00, P = 0.192) or negative (U = 214.00, P = 0.057) scales. All patients were single and lived with parents or guardians. There were no differences in mean treatment time between groups, with 143.75 ± 68 days for quetiapine and 144.1 ± 62.5 for the olanzapine group. Concomitant medications during the study are provided in Table3. There was no difference between groups with regard to the use of any adjunctive medication at baseline or end of study.Decreases in PANSS total score and PANSS subscales were observed in the two treatment groups. Statisti-cally significant decreases between baseline and 6 month assessments were observed in the PANSS total score (W = )2.201, P = 0.028, and W = )2. 197, P = 0.028 for olanzapine and quetiapine groups, respectively), with the end point total score equal to 32.3% of the baseline score in the olanzapine group and 26% of the baseline score in the quetiapine group.

	Fig. 1	Assessed for
		Eligibility
			Not Randomized (n=3)
			-Refused to participate in the study (n=3)
		Randomized
		(n=50)
	Assigned to Quetiapine	Assigned to Olanzapine
	(n=24)		(n=26)
	Total Withdrawn (n=8)		Total Withdrawn (n=9)
	-Loss to Follow-up (n=3)		-Loss to Follow-up (n=4)
	-Poor compliance[?] (n=1)		-Poor compliance[?] (n=0)
	-Symptom Remission (n=0)		-Symptom Remission (n=1)
	-Poor Response (PR) (n=4)		-Poor Response (PR) (n=2)
	-Change to Treatment (n=0)		-Change to Treatment (n=2)
	-Adverse Events (AE) (n=0)		-Adverse Events (AE) (n=0)
	Completed		Completed
	Quetiapine Trial		Olanzapine Trial
	(n=16)		(n=16)

j Symptom reduction Change from baseline within treatment groups

Table 2

 2 Quetiapine and olanzapine doses (mg/day) administered visit-wise

	Visit	Quetiapine		Olanzapine
		Mean	SD	Mean	SD
	Visit 0 (baseline)	116.67	95.46	7.60	2.50
	Visit 1 (day 7)	406.25	259.73	13.37	5.74
	Visit 2 (day 15)	552.50	395.05	14.81	6.71
	Visit 3 (day 30)	618.48	423.45	15.96	8.10
	Visit 4 (day 90)	406.25	200.78	11.25	7.57
	Visit 5 (day 180)	532.81	459.59	9.71	6.55

Table 3

 3 Adjunctive pharmacological treatments during participation in the study

	Quetiapine	Olanzapine
		n	% b	n	% b
	Total patients with adjunctive treatment a	21	87.5	21	80.8
	Anticholinergics	3	12.5	8	30.8
	Beta-blockers	2	8.3	1	3.8
	Benzodiazepines	14	58.3	17	65.4
	Antidepressants	8	33.3	10	38.5
	Antiepileptics	7	29.2	7	26.9
	Lithium	6	25.0	2	7.7
	Analgesics	2	8.3	0	0.0
	Iron compounds	1	4.2	0	0.0
	Non-steroidal anti-inflammatory drugs	1	4.2	0	0.0
	Cough medications	1	4.2	0	0.0

a There were no significant differences between the two treatment groups (Chisquare; P > 0.05) b Percentage calculated according to the total sample (quetiapine n = 24, olanzapine n = 26)

Table 4

 4 Safety and tolerability measures: baseline and 6 months

		Evolution of Quetiapine	vs. Olanzapine	Sig	U = 274.000, P = 0.605	U = 262.500, P = 0.464	U = 244.000, P = 0.660	U = 309.000, P = 0.118	U = 231.500, P = 0.118	U = 263.000, P = 0.340	U = 205.000, P = 0.093	U = 187.500, P = 0.41	U = 122.500, P = 0.026	U = 156.500, P = 0.905	U = 36.000, P = 0.190
		Olanzapine	(Baseline vs. 6 months)	Sig	W = )4.336, P < 0,01	W = )3.769, P < 0,01	W = )2.602, P = 0,009	W = )4.055, P < 0,01	W = )2.366, P = 0.018	W = )0.210, P = 0.833	W = )2.201, P = 0.028	W = )2.201, P = 0.028	W = )2.675, P = 0.007	W = )0.864, P = 0.388	W = 0, P = 1
	Analysis	Quetiapine	(Baseline vs. 6 months)	Sig	W = )3.862, P < 0.01	W = )3.242, P = 0,001	W = )3.530, P < 0,01	W = )4.204, P < 0,01	W = )2.028, P = 0.043	W = )2.533, P = 0.011	W = )1.859, P = 0.063	W = )2. 197, P = 0.028	W = )0.534, P = 0.593	W = )0.943, P = 0.345	W = )1.000, P = 0.317
		6 months		n Mean ± SD	26 3.54 ± 1.30	26 6.34 ± 9.62	26 9.12 ± 7.91	26 61.88 ± 16.01	26 14.04 ± 4.75	26 22.15 ± 7.24	26 35.42 ± 8.88	26 71.62 ± 17.33	22 20.82 ± 5.96	21 22.81 ± 6.35	17 21.71 ± 4.77
	Olanzapine	Baseline		n Mean ± SD	26 5.46 ± 0.86	26 18.73 ± 12.69	24 17.83 ± 10.03	26 37.58 ± 17.33	26 26.12 ± 4.10	26 26.58 ± 8.34	26 52.96 ± 10.84	26 105.65 ± 19.97	21 23.52 ± 5.1	20 23.70 ± 5.29	12 21.50 ± 5.25
		6 months		n Mean ± SD	24 2.96 ± 1.40	24 5.50 ± 6.39	24 8.00 ± 6.70	24 67.79 ± 16.79	24 15.08 ± 4.07	24 16.29 ± 5.15	24 34.45 ± 9.89	24 67.29 ± 17.86	22 24.36 ± 6.15	19 21.63 ± 7.51	10 21.3 ± 5.46
	Quetiapine	Baseline		n Mean ± SD	23 5.04 ± 1.30	23 15.70 ± 12.85	22 17.27 ± 9.69	24 41.17 ± 15.56	24 23.25 ± 7.25	24 21.88 ± 6.835	22 46.05 ± 11.26	22 91.05 ± 21.42	19 24.16 ± 5.08	16 22.13 ± 7.67	7 22.14 ± 4.60
					CGI	YOUNG	HAMILTON	GAF	PANSS Positive	PANSS Negative	PANSS General	PANSS Total	SDQ Patient	SDQ Parent	SDQ Teacher

Table 5

 5 Side effects as measured with the UKU

	Subjective side effect	Quetiapine	Olanzapine
		(n = 24)		(n = 26)
		n (%)		n (%)
		Ever	End point Ever	End point
	Concentration difficulties	16 (67) 6 (37)	18 (72) 9 (56)
	Asthenia/lassitude/increased	19 (79) 9 (56)	19 (73) 9 (53)
	fatigability
	Sleepiness/sedation	19 (79) 11 (69)	21 (84) 12 (71)
	Failing memory	14 (58) 4 (25)	12 (52) 7 (41)
	Depression	9 (37)	8 (50)	11 (44) 8 (47)
	Tension/inner unrest	15 (62) 7 (44)	13 (54) 5 (29)
	Increased duration of sleep	11 (46) 6 (37)	12 (48) 6 (35)
	Reduced duration of sleep	4 (17)	0 (0)	6 (25)	1 (6)
	Increased dream activity	9 (39)	4 (25)	6 (26)	2 (12)
	Emotional indifference Rigidity a,b	7 (29) 4 (17)	3 (19) 0 (0)	14 (56) 6 (35) 7 (29) 0 (0)
	Hypokinesia/akinesia	11 (46) 2 (12)	14 (54) 4 (23)
	Tremor	7 (37)	4 (25)	13 (50) 4 (23)
	Akathisia	6 (26)	0 (0)	8 (32)	3 (18)
	Accommodation disturbances 6 (26) Increased salivation b 10 (42) 2 (12) 2 (12)	7 (32) 13 (52) 2 (12) 5 (29)
	Reduced salivation	9 (39)	4 (25)	2 (8)	1 (6)
	Constipation	10 (42) 1 (6)	7 (27)	1 (6)
	Polyuria/polydipsia	7 (30)	4 (25)	8 (31)	5 (29)
	Orthostatic dizziness	3 (13)	2 (12)	5 (21)	1 (6)
	Palpitations/tachycardia	11 (46) 1 (12)	8 (35)	1 (6)
	Increased tendency to sweat 8 (33)	1 (6)	7 (28)	5 (29)
	Weight gain	13 (72) 8 (50)	20 (91) 15 (88)
	Amenorrhea	1 (20)	0 (0)	4 (50)	0 (0)
	Increased sexual desire	1 (6)	0 (0)	5 (28)	2 (14)
	Dry vagina	0 (0)	0 (0)	2 (22)	0 (0)
	Tension headache	6 (25)	3 (19)	6 (24)	5 (29)

Olanzapine and quetiapine in adolescence


de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

This editorial aims to describe important developments and changes of European Child and Adolescent Psychiatry. We are happy to have observed a gradual rise of the impact factor over the years to 1.997 in 2007. From 2009, the Journal will not only be listed in the Social Science Index (category Developmental Psychology) but also in the Science Citation Index (category Psychiatry). This is a recognition of the status of the Journal in the field of child and adolescent psychiatry and developmental psychopathology. Another welcome development is that we face an increase of the number of submitted papers over the years as well as, even more relevant, improved quality of the submitted work. To accommodate this, the content of the Journal will expand to 12 issues per year in 2009.

From now on, the Journal will also have a new section of ''Letters to the Editor''. These are short communications of 800 words maximum, either or not in reaction to work published in the Journal. For more details, see the instructions for manuscript submission.

To further facilitate the development of the Journal and provide service to authors and co-authors of promising papers, four junior editors have been appointed and joined the editorial team. These are Dr. Pieter Hoekstra (the Netherlands), Dr. Guilherme Polanczyk (Brasil), Dr. Veit Roessner (Germany) and Dr. Benno Graf von Schimmelman (Germany). They will assist the editors in providing in-depth and detailed feedback on interesting papers. All of this with just one aim in mind, to further lift the quality and status of the Journal.

Professors Eric Taylor and Anita Thapar regrettably have announced to quit their job of editor. We are grateful for their many contributions to the Journal over the past years.

J

  10.1007/s00787-009-0751-y ECAP 751