This study examined the early course of depression by testing a conceptual model for the development and remission of depressive symptoms. In this model, prodromal symptoms emanate from the core pathological processes underlying the disorder and comprise the core syndrome as the earliest symptoms to appear, with episodes of depression representing the more pronounced peaks of symptomatology; the core symptoms would also be the last to remit. Several general hypotheses generated from this model were tested. Additionally, the hopelessness and endogenous subtypes of depression were conceptualized within this model and examined. Cognitive risk for depression and the cognitive personality modes of sociotropy and autonomy were also examined as predictors of specific prodromal and residual symptoms. Correlation and survival analyses were conducted to test the various hypotheses. Results supported the existence of a depressive prodrome as well as the general model being tested. The earliest symptoms to appear in an episode of depression were generally consistent throughout the episode and remained as the last to remit. The order of symptom onset was related to the reverse of the order of symptom remission. The durations for the prodromal and remission phases were significantly correlated. When applied to the hopelessness subtype of depression, and depressions experienced by highly sociotropic individuals, the model held. In the endogenous subtype of depression, and among cognitively high-risk and highly autonomous individuals, the model was not strongly supported. / Psychology

Background/Aims: Temperament and mood swings are promising indicators for the characterization of mood spectrum vulnerability. The aim of this study was to investigate the relationship between affective temperament and mood swings in bipolar disorder. We explored these clinical features retrospectively. Methods: Patients who met the criteria for bipolar I disorder were enrolled in the study. Exclusion criteria were partial remittance and a full affective or psychotic episode. Data concerning illness and family history, mood swings (semistructured interview for mood swings) and depression (Beck, Depression Inventory) were obtained. We examined premorbid temperament with the validated German version Temps-M of the original version Temps-A. Patients with and without mood swings were compared with respect to the dominant temperament. Results: Out of 20 bipolar patients, 6 subjects reported mood swings prior to the onset of affective disorder. Subjects with mood swings prior to the onset of bipolar disorder significantly correlated with a positive family history of affective disorders. Concerning cyclothymic and irritable temperament, bipolar affective patients with mood swings had higher scores. No differences were found between males and females. Conclusion: Our findings go in line with previous results that mood swings, as represented by the cyclothymic temperament, are present prior to the first onset of bipolar disorder in a subset of patients. These traits may represent vulnerability markers and could presumably be used to identify individuals at high risk for developing bipolar disorder in order to prevent this illness. Further studies are indicated to clarify the correlation with genetic risk factors.

Schizophrenia is a debilitating disorder with an array of affective, cognitive, and behavioral consequences. In addition to these impairments, research suggests that there is a distinct pattern of hedonic functioning in schizophrenia that may contribute to some of the most intractable symptoms of the disorder, the negative symptoms. Specifically, individuals with schizophrenia appear to experience deficient levels of pleasure during anticipation of a pleasurable stimulus, while experiencing typical levels of pleasure while directly engaged with a pleasurable stimulus. Despite these findings, it is unclear whether hedonic functioning deficits occur in individuals with subthreshold levels of psychotic symptoms and/or in individuals at clinical high risk for the disorder. The purpose of this study was to examine hedonic functioning in relation to the continuum of psychotic symptoms in a college undergraduate student sample, and in those at clinical risk for schizophrenia. Participants were 679 students who completed self-report measures of current psychotic-like experiences, and trait-like components of hedonic functioning (i.e., anticipatory and consummatory pleasure). Consistent with study hypotheses, deficits in anticipatory pleasure, but not in consummatory pleasure, were significantly associated with increased clinical risk for schizophrenia. However, this relation was found exclusively among women in the sample, whereas men did not show a significant relation between anticipatory pleasure deficits and clinical high-risk. Furthermore, anticipatory pleasure deficits were not significantly associated with increases in the number of positive psychotic symptoms endorsed. Moreover, consummatory pleasure was not associated with increases in the number of subthreshold positive psychotic symptoms, nor was there a relation with the number of distressing positive psychotic symptoms or clinical risk status. The present study provides the first examination of the relation between hedonic functioning and subthreshold psychotic symptoms, as well as the relation with clinical high-risk for psychosis. These findings suggest that anticipatory pleasure deficits may be more closely related to increased clinical risk for psychosis among women rather than increases in psychotic symptoms in the general population. Anticipatory pleasure deficits may be a useful target for intervention and prevention techniques among those at clinical risk for psychosis, especially in female at risk populations. Additional longitudinal studies will be essential for testing whether anticipatory pleasure deficits predict the occurrence of future psychotic disorders among those at high risk for the disorder in order to improve early identification and early intervention efforts in this population. / Psychology

Οι ασθενείς με σχιζοφρένεια βρίσκονται σε υψηλό κίνδυνο για αυτοκτονικό ιδεασμό, απόπειρες αυτοκτονίας, και επιτυχημένες απόπειρες. Παρ’ όλα αυτά, η αυτοκτονική συμπεριφορά κατά τη διάρκεια της πρόδρομης περιόδου της σχιζοφρένειας και μια πιθανή συσχέτιση μεταξύ της πρόδρομης αυτοκτονικής συμπεριφοράς και της αυτοκτονικότητας μετά την έναρξη της ενεργούς ψυχώσεως δεν είχε μελετηθεί. 106 συνεχόμενες εισαγωγές ασθενών με πρόσφατη έναρξη σχιζοφρένειας εκτιμήθηκαν αναδρομικά για πρόδρομα συμπτώματα και αυτοκτονικότητα κατά τη διάρκεια της πρόδρομης φάσης καθώς και μετά την έναρξη της ενεργούς ψυχώσεως. Επιπρόσθετα, 106 σταθμισμένοι μάρτυρες από το γενικό πληθυσμό εκτιμήθηκαν για αυτοκτονική συμπεριφορά κατά τη διάρκεια της ίδιας περιόδου με την πρόδρομη φάση του αντίστοιχου ασθενή. Αυτοκτονικός ιδεασμός και απόπειρες αυτοκτονίας κατά τη διάρκεια της πρόδρομης περιόδου βρέθηκαν στο 25.5% και 7.5% των ασθενών το οποίο είναι αντίστοιχα 3.8 φορές και 8 φορές πιο συχνό από ότι στους μάρτυρες. Οι ασθενείς με αυτοκτονική συμπεριφορά είχαν μεγαλύτερο αριθμό πρόδρομων συμπτωμάτων από ότι οι ασθενείς χωρίς αυτοκτονική συμπεριφορά. Η πρόδρομη καταθλιπτική διάθεση, η εκσεσημασμένη έκπτωση στη λειτουργικότητα, και το κάπνισμα καπνού βρέθηκαν να ασκούν ανεξάρτητη επίδραση στον αυτοκτονικό ιδεασμό, ενώ η καταθλιπτική διάθεση ήταν το πρόδρομο σύμπτωμα σημαντικά πιο συχνό στους ασθενείς με απόπειρες αυτοκτονίας. Οι απόπειρες αυτοκτονίας συσχετίστηκαν με πρώιμη έναρξη της πρόδρομης συμπτωματολογίας και της ενεργού ψυχώσεως. Όλοι οι ασθενείς με απόπειρα αυτοκτονίας στην πρόδρομη περίοδο ήταν καπνιστές. Ο αυτοκτονικός ιδεασμός κατά τη διάρκεια της πρόδρομης φάσης είχε ισχυρή συσχέτιση με την δια βίου αυτοκτονικότητα μετά την έναρξη της ενεργούς ψυχώσεως. Συμπερασματικά, η αυτοκτονική συμπεριφορά είναι αρκετά συχνή κατά τη διάρκεια της πρόδρομης περιόδου. Ο συνδυασμός καπνίσματος, καταθλιπτικής διάθεσης, έκπτωσης λειτουργικότητας, και ενός μεγάλου αριθμού προδρόμων συμπτωμάτων, ειδικά σε ασθενείς με πρώιμη έναρξη συμπτωματολογίας, συνεπάγεται σημαντικά αυξημένο κίνδυνο αυτοκτονικού ιδεασμού. Ιδιαίτερη προσοχή απαιτούν οι ασθενείς με αυτοκτονικό ιδεασμό κατά την πρόδρομη περίοδο μετά την έναρξη της ενεργούς ψυχώσεως διότι ο κίνδυνος απόπειρας αυτοκτονίας είναι υψηλός. / Patients with schizophrenia are at high risk for suicide ideation, attempts and completed suicide. However, suicidal behavior during the prodromal phase of schizophrenia and a possible association between prodromal suicidal behavior and suicidality after the onset of overt psychosis are not studied. 106 consecutively admitted schizophrenia patients with recent onset were evaluated retrospectively for prodromal symptoms and suicidality during the prodromal phase and after the onset of frank psychosis. Additionally, 106 matched control subjects from the general population were evaluated for suicidality during the same age period of the prodromal phase of the corresponding patient. Suicide ideation and attempt during the prodromal period were reported in 25.5% and 7.5% of the patients that is 3.8-fold and 8-fold greater than in the controls, respectively. Patients with suicidal behavior experienced a greater number of prodromal symptoms than those without. Prodromal depressive mood, marked impairment in role functioning, and tobacco smoking exerted an independent effect on suicide ideation, whereas depressive mood was the symptom significantly more frequent in patients with suicide attempt. Suicide attempts were associated with an earlier onset of prodromal symptoms and frank psychosis. All patients with prodromal suicide attempts were cigarette smokers. Suicide ideation during the prodromal phase was strongly associated with lifetime suicidality after the onset of frank psychosis. In conclusion suicidal behavior is quite common during the prodromal period. The association of smoking, depressive mood, impaired functioning, and a large number of prodromal symptoms, particularly in patients with an early onset of symptoma¬tology carries a substantially increased risk for suicide ideation. Particular care is needed in patients with prodromal suicide ideation after the onset of frank psychosis because the risk to attempt suicide is high.

Background/Aims: Temperament and mood swings are promising indicators for the characterization of mood spectrum vulnerability. The aim of this study was to investigate the relationship between affective temperament and mood swings in bipolar disorder. We explored these clinical features retrospectively. Methods: Patients who met the criteria for bipolar I disorder were enrolled in the study. Exclusion criteria were partial remittance and a full affective or psychotic episode. Data concerning illness and family history, mood swings (semistructured interview for mood swings) and depression (Beck, Depression Inventory) were obtained. We examined premorbid temperament with the validated German version Temps-M of the original version Temps-A. Patients with and without mood swings were compared with respect to the dominant temperament. Results: Out of 20 bipolar patients, 6 subjects reported mood swings prior to the onset of affective disorder. Subjects with mood swings prior to the onset of bipolar disorder significantly correlated with a positive family history of affective disorders. Concerning cyclothymic and irritable temperament, bipolar affective patients with mood swings had higher scores. No differences were found between males and females. Conclusion: Our findings go in line with previous results that mood swings, as represented by the cyclothymic temperament, are present prior to the first onset of bipolar disorder in a subset of patients. These traits may represent vulnerability markers and could presumably be used to identify individuals at high risk for developing bipolar disorder in order to prevent this illness. Further studies are indicated to clarify the correlation with genetic risk factors.

Family functioning has long been a focus of research in psychopathology. Decades of research has shown that family factors are associated with symptom severity, relapse, functional outcomes, and conversion to psychosis among at-risk individuals. Previous studies suggest family functioning varies across cultures, which raises the possibility that associations between family factors and psychopathology may also differ by culture. Furthermore, family functioning assessment generally involves instruments that have not been systematically validated for use with individuals from diverse cultural backgrounds. The current study used data from the Adolescent Brain Cognitive Development study (N = 11,138) to: (1) evaluate three family functioning scales (i.e., Family Environment Scale, Child's Report of Parental Behavior Inventory, Parental Monitoring Survey) and the Prodromal Questionnaire – Brief Child version for measurement invariance across racial/ethnic groups; (2) investigate the relations between family factors and psychosis; and (3) compare relations derived from Step 2 between racial/ethnic groups. Full scalar invariance was tenable for the CRPBI and the PQ-BC, providing statistical support for mean comparisons across groups. The FES and the PMQ lacked scalar invariance, which suggests mean comparisons across groups may not be appropriate. The CRPBI and the PMQ are significantly associated with the PQ-BC, and all three family scales had equivalent relations with the PQ-BC across groups. The current study highlights the importance of evaluating assessment instruments for measurement invariance across racial/ethnic groups. Results also help to connect specific family factors to the etiology of psychotic disorders among US children and adolescents.

Two main psychopathology-based approaches to detection of the prodrome have emerged; the Ultra High Risk (UHR) and Basic Symptom approaches. Conversion risk varies between studies using these approaches and in one centre conversion rates are reported to be decreasing year on year. There is a need examine the conversion risk across studies to establish a pooled estimate of risk for instruments designed to detect the prodrome of psychosis. To maximise the detection of those thought to present a risk of psychosis the Lancashire Early Assessment and Detection (LEAD) clinic uses an UHR instrument, the Comprehensive Assessment of at Risk Mental States (CAARMS) and A Basic Symptom instrument, the Schizophrenia Proneness Instrument (SPI-A). The thesis had two broad aims 1) to conduct a systematic review with meta-analysis of the research field to date and identify areas for further research, 2) to establish the accuracy of the LEAD clinic predictions. The meta-analysis involved a systematic search of MEDLINE, EMBASE, PsychINFO and CINHAL identifying studies of psychopathology-based instruments for the detection of the psychosis prodrome. The service evaluation examined for conversion to psychosis in patients examined for Basic Symptoms (SPI-A), attenuated positive symptoms (CAARMS), schizotypy (SPQ-A) and social functioning (SOFAS).The meta-analysis found that both the UHR and Basic Symptom approaches yield similar results. The differences in the positive predictive values (PPV) of the two approaches were not significant (Basic Symptoms, 0.34, UHR 0.25). The service evaluation found over a third (n=58) of referrals to the LEAD clinic to be psychotic at baseline and sixty-four patients to have an at risk mental state (ARMS). Conversion risk for CAARMS was 36.67%. and was 28.57% for SPI-A. The COGDIS criterion of SPI-A was found to be the most predictive with a PPV of 0.43, a sensitivity of 0.80. When patients met a combination of both COGDIS and CAARMS the likelihood ratio increased to 5.25 although the sensitivity was low (0.47).Overall, the findings of the thesis indicate that both the Basic Symptom and UHR approaches are valid for use in routine clinical settings for the assessment of psychosis risk. The thesis found that a combination of both approaches could provide future opportunities research. The SPQ-A schizotypy assessment was found to correlate with the attenuated symptom criterion of CAARMS and evidence suggests that the SPQ-A score increases closer to transition. The SPQ-A could offer opportunities for developing efficient methods of monitoring progression of prodromal symptoms.

La psychose est un syndrome apparaissant progressivement à l’adolescence chez des individus à risque selon un processus dynamique appelé transition psychotique. Ces individus à risque sont repérables cliniquement mais les données biologiques actuelles sont insuffisantes pour expliquer l’apparition de la psychose. Au cours de cette thèse, nous avons cherché à identifier les facteurs biologiques responsables de ce processus. Les hypothèses permettant d’expliquer la transition psychotique privilégient l’interaction gène x environnement, sous-tendue par des mécanismes épigénétiques. Nous avons mené une étude des modifications de la méthylation de l’ADN et de la transcription à l’aide de techniques de biologie moléculaire et de bio-informatique à l’échelle pan-génomique. La transition psychotique semble être liée à des modifications de méthylation et de transcription de gènes impliqués dans des mécanismes comme le guidage axonal ou la régulation du stress oxydatif. Ces modifications longitudinales pourraient refléter l’influence de l’environnement. Les facteurs environnementaux pourraient déréguler l’axe biologique du stress dès les phases précoces de la maladie, comme le suggère l’augmentation de la sécrétion de cortisol basal que nous avons montré chez les individus à risque. En outre, il est probable que des spécificités au niveau des gènes et des processus régulant l’épigénome soient également impliquées dans cette réponse individuelle à l’environnement. Nous avons montré l’importance du métabolisme mono-carboné au moins dans un sous-groupe spécifique de patients. Ces résultats doivent être répliqués et étendus dans d’autres paradigmes pour valider l’implication de ces processus dans la transition psychotique. En cas de confirmation, ces voies biologiques pourraient s’avérer être des pistes intéressantes pour développer des thérapeutiques ciblées et relever le défi de la prévention de la psychose chez des individus à risque. / Psychosis is a progressive mental disorder which normally occurs during adolescence in at-risk subjects following a dynamic process termed “psychotic transition”. These at-risk subjects are clinically identifiable but biological data are still insufficient in explaining the onset of psychosis. Throughout this thesis, we aim to identify biological factors implicated in this pathophysiological process. Current hypotheses explaining the psychotic transition favor the interaction between genes and the environment mediated by epigenetic mechanisms. We conducted studies examining methylomic and transcriptomic changes during psychotic transition using molecular biology and bioinformatics techniques at a whole genome scale. Our results suggest that psychotic transition may be linked to methylomic and transcriptomic changes in genes implicated in axon guidance or oxidative stress. These longitudinal changes could be related to environmental factors. Some of these factors could deregulate the hormonal stress response at the earliest phases of psychosis. Indeed, our results show that secretion of basal cortisol is increased in prodromal individuals. Moreover, it is likely that genes and processes regulating epigenetic modifications are also implicated in the individual response to the environment. We have shown the importance of the one-carbon metabolism for at least one sub-group of patients affected by psychosis. Our results should be replicated using other paradigms in order to definitively validate the implication of these various actors in the psychotic transition. If confirmed, knowledge of these biological mechanisms could lead to the development of targeted therapeutics to prevent psychosis in at-risk individuals.