Investigation of structural brain correlates of neurological soft signs in individuals at ultra-high risk for psychosis.

Increased severity of neurological soft signs (NSS) in schizophrenia have been associated with abnormal brain morphology in cerebello-thalamo-cortical structures, but it is unclear whether similar structures underlie NSS prior to the onset of psychosis. The present study investigated the relationship between severity of NSS and grey matter volume (GMV) in individuals at ultra-high risk for psychosis (UHR) stratified for later conversion to psychosis. Structural T1-weighted MRI scans were obtained from 56 antipsychotic-naïve UHR individuals and 35 healthy controls (HC). The UHR individuals had follow-up data (mean follow-up: 5.2 years) to ascertain clinical outcome. Using whole-brain voxel-based morphometry, the relationship between NSS and GMV at baseline was assessed in UHR, HC, as well as individuals who later transitioned (UHR-P, n = 25) and did not transition (UHR-NP, n = 31) to psychosis. NSS total and subscale scores except motor coordination were significantly higher in UHR compared to HC. Higher signs were also found in UHR-P, but not UHR-NP. Total NSS was not associated with GMV in the whole sample or in each group. However, in UHR-P individuals, greater deficits in sensory integration was associated with lower GMV in the left cerebellum, right insula, and right middle frontal gyrus. In conclusion, NSS are present in UHR individuals, particularly those who later transitioned to a psychotic disorder. While these signs show little overall variation with GMV, the association of sensory integration deficits with lower GMV in UHR-P suggests that certain brain areas may be implicated in the development of specific neurological abnormalities in the psychosis prodrome.

The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): a randomised, double-blind, placebo-controlled, multicentre clinical trial.

BACKGROUND: Medication is commonly used to treat youth depression, but whether medication should be added to cognitive behavioural therapy (CBT) as first-line treatment is unclear. We aimed to examine whether combined treatment with CBT and fluoxetine was more effective than CBT and placebo in youth with moderate-to-severe major depressive disorder. METHODS: The Youth Depression Alleviation-Combined Treatment (YoDA-C) trial was a randomised, double-blind, placebo-controlled, multicentre clinical trial. Participants were aged 15-25 years with moderate-to-severe MDD and had sought care at one of four clinical centres in metropolitan Melbourne, Australia. Patients were randomly assigned (1:1) to receive CBT for 12 weeks, plus either fluoxetine or placebo. Participants began on one 20 mg capsule of fluoxetine or one placebo pill per day. All participants received CBT, delivered by therapists in weekly 50-minute sessions and attended interviews at baseline, and at weeks 4, 8, and 12, during which they completed assessments with research assistants. Participants saw a psychiatrist or psychiatry trainee to complete medical assessments at the same timepoints. The primary outcome was change in the interviewer-rated Montgomery-Åsberg Depression Rating Scale (MADRS) score at 12 weeks. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612001281886). FINDINGS: 153 participants (mean age 19·6 years [SD 2·7]) were enrolled from Feb 20, 2013, to Dec 13, 2016. 77 (50%) patients were allocated to CBT and placebo and 76 (50%) to CBT and fluoxetine. Participants had severe depression at baseline (mean MADRS score 33·6 [SD 5·1] in the CBT and placebo group and 32·2 [5·6] in the CBT and fluoxetine group), with high proportions of participants with anxiety disorder comorbidity (47 [61%] in the CBT and placebo group and 49 [64%] in the CBT and fluoxetine group) and past-month suicidal ideation (55 [71%] in the CBT and placebo group and 59 [78%] in the CBT and fluoxetine group). 59 (77%) participants in the CBT and placebo group and 64 (84%) in the CBT and fluoxetine group completed follow-up at week 12. After 12 weeks of treatment both groups showed a reduction in MADRS scores (-13·7, 95% CI -16·0 to -11·4, in the CBT and placebo group and -15·1, -17·4 to -12·9, in the CBT and fluoxetine group). There was no significant between-group difference in MADRS scores (-1·4, -4·7 to 1·8; p=0·39). There were five suicide attempts in the CBT and placebo group and one suicide attempt in the CBT and fluoxetine group (odds ratio 0·2, 0·0-1·8; p=0·21), and no significant between-group differences for other suicidal behaviours. INTERPRETATION: We did not find evidence that the addition of fluoxetine (rather than placebo) to CBT further reduced depressive symptoms in young people with moderate-to-severe MDD. Exploratory analyses showed that the addition of medication might be helpful for patients with comorbid anxiety symptoms and for older youth. FUNDING: Australian National Health and Medical Research Council.

The Youth Mood Clinic: an innovative service for the treatment of severe and complex depression.

OBJECTIVE: Depression is the leading cause of disability for Australians from late adolescence through mid-adulthood, and effective treatments can positively impact subsequent life course trajectories. A treatment model for the management of complex youth depression, characterised by symptom severity, multi-morbidity and ongoing suicidality is presented. CONCLUSIONS: The Youth Mood Clinic (YMC) provides multidisciplinary, team-based treatment for young people aged 15-25 years. The YMC model utilises a phased treatment approach, drawing on elements of cognitive and interpersonal psychotherapy embedded within case management and psychiatry review. Particular attention is given to developmental factors, engagement, assessment, suicide risk, caregiver input and pharmacotherapy. Key tasks of the YMC treatment phases are outlined, reflecting initial stages, recovery planning and treatment, continuation, consolidation and future planning.

The initial prodrome to bipolar affective disorder: prospective case studies.

BACKGROUND: The initial prodrome to bipolar disorder has received very little attention to date, with most of the available data only addressing the prodrome to relapse. This study presents several prospective case studies of the initial prodrome to bipolar affective disorder. METHODS: Three patients are presented who developed bipolar disorder during their treatment at the Personal Assessment and Crisis Evaluation Clinic (PACE). They were prospectively interviewed over a 12-month period using standard clinical research interviews. RESULTS: These patients met the criteria for bipolar disorder by the end of the treatment period. Depressive symptoms were the main reason for their first clinical presentation, with mania developing at a later date. Other comorbidities were observed before they were diagnosed with bipolar disorder. LIMITATIONS: The generalisability of our findings was constrained because of the small sample size. Furthermore, our findings are likely to be influenced by the intake criteria used at PACE, a clinic that primarily aims at identifying patients at risk of psychosis rather than bipolar disorder. CONCLUSION: Our study provides information about the initial prodrome to bipolar disorder, which has previously been neglected in research studies. We found there were no prodrome features that clearly distinguished between patients who go on to develop bipolar disorder and those who develop schizophrenia. We hope our prospective data will be the starting point for subsequent studies, with the aim of applying these findings to developing suitable preventative interventions for bipolar disorder.

The PACE Clinic: identification and management of young people at "ultra" high risk of psychosis.

Over the past decade, both clinical and research interest in the early stages of psychotic disorders has grown. This has been associated with research suggesting that early intervention in these disorders may limit their impact on the life of the affected individual and his or her family. It has also been recognized that the biological and psychological changes underpinning the development of psychotic disorders may already be active in the prepsychotic or prodromal phase. It has been suggested that efforts to prevent psychotic disorders should be focused on this phase of emerging illness. In this article, the authors review work conducted at the PACE Clinic in Melbourne, Australia since 1994. This clinical research program was established to develop strategies for identifying young people at high risk for developing a psychotic disorder within a short period. The program has also investigated biological and psychological processes thought to underlie the development of psychosis and evaluated potential preventive interventions.