Impact of childhood trauma on antipsychotic effectiveness in schizophrenia spectrum disorders: A prospective, pragmatic, semi-randomized trial.

Antipsychotic medications are generally effective in ameliorating psychotic symptoms in schizophrenia spectrum disorders (SSDs). Identifying predictors associated with poor treatment response is important for a personalized treatment approach. Childhood trauma (CT) may have a general and differential effect on the effectiveness of different types of antipsychotics in SSDs. The Bergen-Stavanger-Trondheim-Innsbruck (BeSt InTro) study is a pragmatic, researcher-initiated, semi-randomized trial. The present study aimed to investigate symptom change (the Positive and Negative Syndrome Scale) from baseline to 1, 3, 6, 12, 26, 39 and 52 weeks of antipsychotic treatment (amisulpride, aripiprazole and olanzapine) by group (CT/no CT). Participants (n = 98) with diagnoses within the schizophrenia spectrum (F20-29 in the International Classification of Diseases - 10th Revision) were randomized to receive amisulpride, aripiprazole or olanzapine, and for this study categorized into groups of none and low CT, and moderate to severe CT according to thresholds defined by the Childhood Trauma Questionnaire Short-Form manual. CT in SSDs predicted an overall slower treatment response and less antipsychotic effectiveness after 26 weeks of treatment, which was statistically nonsignificant at 52 weeks. Secondary analyses showed a differential effect of CT related to type of antipsychotic medication: patients with SSDs and CT who received olanzapine showed less antipsychotic effectiveness throughout 52 weeks of treatment. The intention-to-treat and per-protocol analyses were convergent. Our findings indicate that in patients with SSD and CT, delayed response to antipsychotics could be expected, and a longer evaluation period before considering change of medication may be recommended.

Neurocognitive development in first episode psychosis 5 years follow-up: associations between illness severity and cognitive course.

Cognitive deficits are documented in first-episode psychosis (FEP), but the continuing course is not fully understood. The present study examines the longitudinal development of neurocognitive function in a five year follow-up of FEP-patients, focusing on the relation to illness severity, as measured by relapses and diagnostic subgroups. The study is an extension of previous findings from the TIPS-project, reporting stability over the first two years. Sixty-two FEP patients (53% male, age 28 ± 9 years) were neuropsychologically examined at baseline and at 1, 2, and 5 year follow-ups. The test battery was divided into five indices; Verbal Learning, Executive Function, Impulsivity, Motor Speed, and Working Memory. To investigate the effect of illness severity, the sample was divided in groups based on number of relapses, and diagnostic subgroups, respectively. Impulsivity and Working Memory improved significantly in the first two years, followed by no change over the next three years. Motor Speed decreased significantly from 2 to 5 years. Number of relapses was significantly related to Verbal Learning and Working Memory, showing a small decrease and less improvement, respectively, in patients with two or more episodes. No significant association was found with diagnostic group. Neurocognitive stability as well as change was found in a sample of FEP-patients examined repeatedly over 5 years. Of potential greater importance for understanding how psychotic illnesses progress, is the finding of significant associations between neurocognition and number of relapses but not diagnostic group, indicating that neurocognition is more related to recurring psychotic episodes than to the descriptive diagnosis per se.

No change in myonuclear number during muscle unloading and reloading.

Muscle fibers are the cells in the body with the largest volume, and they have multiple nuclei serving different domains of cytoplasm. A large body of previous literature has suggested that atrophy induced by hindlimb suspension leads to a loss of "excessive" myonuclei by apoptosis. We demonstrate here that atrophy induced by hindlimb suspension does not lead to loss of myonuclei despite a strong increase in apoptotic activity of other types of nuclei within the muscle tissue. Thus hindlimb suspension turns out to be similar to other atrophy models such as denervation, nerve impulse block, and antagonist ablation. We discuss how the different outcome of various studies can be attributed to difficulties in separating myonuclei from other nuclei, and to systematic differences in passive properties between normal and unloaded muscles. During reload, after hindlimb suspension, a radial regrowth is observed, which has been believed to be accompanied by recruitment of new myonuclei from satellite cells. The lack of nuclear loss during unloading, however, puts these findings into question. We observed that reload led to an increase in cross sectional area of 59%, and fiber size was completely restored to the presuspension levels. Despite this notable growth there was no increase in the number of myonuclei. Thus radial regrowth seems to differ from de novo hypertrophy in that nuclei are only added during the latter. We speculate that the number of myonuclei might reflect the largest size the muscle fibers have had in its previous history.

Flat affect and social functioning: a 10 year follow-up study of first episode psychosis patients.

BACKGROUND: Affective flattening has been described as enduring, but long term follow-up studies of first episode psychosis patients are lacking. OBJECTIVE: The aim of this study was to follow the symptom development of flat affect (FA), over a 10 year follow-up period, with focus on prevalence, predictors and outcome factors including social functioning. METHODS: Three-hundred-and-one patients with FEP were included at baseline, 186 participated in the 10 year follow-up. These were followed on PANSS item N1 (FA) from baseline through 5 follow-up assessments over 10 years. Patients were grouped as having never-present, improving, deteriorating, fluctuating or enduring FA. The groups were compared on baseline variables, variables at 10 year follow-up, and social functioning throughout the follow-up period. RESULTS: Twenty nine percent never displayed FA, 66% had improving, deteriorating or fluctuating FA, while 5% of patients had enduring FA. Premorbid social function predicted enduring FA. The patients with enduring, fluctuating and deteriorating FA did poorer on all outcome variables, including remission and recovery rates. The enduring FA group did significantly poorer in social functioning over the 10 year period. CONCLUSIONS: FA is expressed at some point of time in the majority of FEP patients in a 10 year follow-up period, and appears more fluctuant than expected from the relevant literature. FA is associated with poorer outcome after 10 years, and enduring FA to poorer social function at all points of assessment.

Apathy in first episode psychosis patients: a ten year longitudinal follow-up study.

BACKGROUND: Apathy is a common symptom in first episode psychosis (FEP), and is associated with poor functioning. Prevalence and correlates of apathy 10 years after the first psychotic episode remain unexplored. OBJECTIVE: The aims of the study were twofold: 1) to examine prevalence and predictors of apathy at 10 years, and 2) to examine the relationship between apathy at 10 years and concurrent symptoms, functioning and outcome, including subjective quality of life. METHODS: Three-hundred-and-one patients with FEP were included at baseline, 186 participated in the 10 year follow-up. Of these, 178 patients completed the Apathy Evaluation Scale (AES-S-Apathy). Patients were classified as having apathy (AES-S-Apathy≥27) or not. The relationship between apathy and baseline variables (Demographics, Diagnosis, Duration of Untreated Psychosis), measures of symptomatology (Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia), functioning (Global Assessment of Functioning Scale, Strauss Carpenter Level of Functioning Scale) and subjective quality of life (Lehman's Quality of Life Interview) were estimated through correlation analyses and blockwise multiple hierarchical regression analysis. RESULTS: Nearly 30% of patients met the threshold for being apathetic at follow-up. No baseline variables predicted apathy significantly at 10 years. Apathy was found to contribute independently to functioning and subjective quality of life, even when controlling for other significant correlates. CONCLUSIONS: Apathy is a common symptom in a FEP cohort 10 years after illness debut, and its presence relates to impaired functioning and poorer subjective quality of life.

Patient satisfaction with treatment in first-episode psychosis.

PURPOSE: To examine first-episode psychotic patients' satisfaction with elements of a comprehensive 2-year treatment program. SUBJECTS AND METHOD: The TIPS (Early Treatment and Intervention in Psychosis) project provided a 2-year treatment program consisting of milieu therapy (inpatient), individual psychotherapy, family intervention and medication. Of 140 patients at baseline, 112 were included at 2-year follow-up. Eighty-four participants were interviewed using a questionnaire eliciting levels of satisfaction with different treatment elements at two of the four sites. RESULTS: Participants and non-participants did not differ on demographic or clinical data at baseline. Of those participating, 75% were satisfied with treatment in general. Individual and milieu therapy received higher rating than medication or family intervention. No predictors of general satisfaction with treatment were found, but continuously psychotic patients were the least satisfied with medication treatment. DISCUSSION: As in most patient satisfaction studies within mental health treatment networks, there was high level of general satisfaction with the total package of treatment but considerable variation in satisfaction for specific interventions. In this sample of first-episode psychosis patients, there was general satisfaction with treatments based on one-to-one relationships while multi-family group intervention was consistently valued less enthusiastically.

Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty: a randomized study.

BACKGROUND: Total knee arthroplasty (TKA) is associated with intense post-operative pain. Besides providing optimal analgesia, reduction in side effects and enhanced mobilization are important in this elderly population. The adductor-canal-blockade is theoretically an almost pure sensory blockade. We hypothesized that the adductor-canal-blockade may reduce morphine consumption (primary endpoint), improve pain relief, enhance early ambulation ability, and reduce side effects (secondary endpoints) after TKA compared with placebo. METHODS: Patients aged 50-85 years scheduled for TKA were included in this parallel double-blind, placebo-controlled randomized trial. The patients were allocated to receive a continuous adductor-canal-blockade with intermittent boluses via a catheter with either ropivacaine 0.75% (n = 34) or placebo (n = 37) (http://www.clinicaltrials.gov Identifier: NCT01104883). RESULTS: Seventy-five patients were randomized in a 1 : 1 ratio and 71 patients were analyzed. Morphine consumption from 0 to 24 h was significantly reduced in the ropivacaine group compared with the placebo group (40 ± 21 vs. 56 ± 26 mg, P = 0.006). Pain was significantly reduced in the ropivacaine group during 45 degrees flexion of the knee (P = 0.01), but not at rest (P = 0.06). Patients in the ropivacaine group performed the ambulation test, the Timed-Up-and-Go (TUG) test, at 24 h significantly faster than patients in the placebo group (36 ± 17 vs. 50 ± 29 s, P = 0.03). CONCLUSION: The adductor-canal-blockade significantly reduced morphine consumption and pain during 45 degrees flexion of the knee compared with placebo. In addition, the adductor-canal-blockade significantly enhanced ambulation ability assessed by the TUG test.

Involuntary hospitalization of first-episode psychosis with substance abuse during a 2-year follow-up.

OBJECTIVE: To investigate whether substance abuse (alcohol or illegal drugs) in patients with first-episode psychosis (FEP) influenced treatment outcomes such as involuntary hospitalization during follow-up. METHOD: First-episode psychosis patients (n = 103) with consecutive admissions to a comprehensive early psychosis program were included and followed for 2 years. Assessment measures were the Positive and Negative Syndrome Scale, Global Assessment of Functioning, and the Clinician Rating Scale (for substance abuse). RESULTS: Twenty-four per cent of patients abused either alcohol or drugs at baseline. The dropout rate at 2 years was the same for substance abusers as for non-abusers. Substance use was not reduced over the 2-year period. At 2-year follow-up, 72% of substance abusers and 31% of non-abusers had experienced at least one occasion of involuntary hospitalization. Patients with substance abuse had significantly higher risk for involuntary hospitalization during follow-up (OR 5.2). CONCLUSION: To adequately treat patients with FEP, clinicians must emphasize treatment of the substance abuse disorder, as well as the psychotic illness. Patients with defined comorbid substance use disorders and FEP are likely to have poorer treatment response than those with psychosis alone.

Contrasting monosymptomatic patients with hallucinations and delusions in first-episode psychosis patients: a five-year longitudinal follow-up study.

BACKGROUND: The main aim of this study was to identify subgroups of patients characterized by having hallucinations only or delusions only and to examine whether these groups differed with regard to demographic characteristics, clinical characteristics and outcome factors, including suicidality. METHODS: Out of 301 consecutively admitted patients with first-episode psychosis, individuals with delusions only (D) and hallucinations only (H) were identified based on Positive and Negative Syndrome Scale (PANSS) items P1 (delusions) and P3 (hallucinations) scores at baseline and through 4 follow-up interviews over 5 years. The subgroups were compared with regard to demographic data, premorbid functioning, duration of untreated psychosis, clinical variables, time to remission and suicidality. RESULTS: Two groups of patients were identified; H (n = 16) and D (n = 106). 179 patients experienced both hallucinations and delusions (dual symptom group). The H group was significantly younger, had a longer duration of untreated psychosis, poorer premorbid function and better insight than the D group. Notably, the H group scored higher on measures of suicidality, and at 5 years follow-up a significantly higher proportion of patients was lost to suicide in this group. The dual symptom group was closer to the D group on significant parameters, including suicidality and suicide rate. CONCLUSIONS: Patients with hallucinations only can be separated from patients with delusions only and the subgroups differ with regard to demographical data, clinical variables and notably with regard to suicidality. These findings suggest distinctions in the underlying biological and psychological processes involved in hallucinations and in delusions.

Early detection of psychosis: positive effects on 5-year outcome.

BACKGROUND: During the last decades we have seen a new focus on early treatment of psychosis. Several reviews have shown that duration of untreated psychosis (DUP) is correlated to better outcome. However, it is still unknown whether early treatment will lead to a better long-term outcome. This study reports the effects of reducing DUP on 5-year course and outcome. METHOD: During 1997-2000 a total of 281 consecutive patients aged >17 years with first episode non-affective psychosis were recruited, of which 192 participated in the 5-year follow-up. A comprehensive early detection (ED) programme with public information campaigns and low-threshold psychosis detection teams was established in one healthcare area (ED-area), but not in a comparable area (no-ED area). Both areas ran equivalent treatment programmes during the first 2 years and need-adapted treatment thereafter. RESULTS: At the start of treatment, ED-patients had shorter DUP and less symptoms than no-ED-patients. There were no significant differences in treatment (psychotherapy and medication) for the 5 years. Mixed-effects modelling showed better scores for the ED group on the Positive and Negative Syndrome Scale negative, depressive and cognitive factors and for global assessment of functioning for social functioning at 5-year follow-up. The ED group also had more contacts with friends. Regression analysis did not find that these differences could be explained by confounders. CONCLUSIONS: Early treatment had positive effects on clinical and functional status at 5-year follow-up in first episode psychosis.

Early identification of non-remission in first-episode psychosis in a two-year outcome study.

OBJECTIVE: To identify predictors of non-remission in first-episode, non-affective psychosis. METHOD: During 4 years, we recruited 301 patients consecutively. Information about first remission at 3 months was available for 299 and at 2 years for 293 cases. Symptomatic and social outcomes were assessed at 3 months, 1 and 2 years. RESULTS: One hundred and twenty-nine patients (43%) remained psychotic at 3 months and 48 patients (16.4%) remained psychotic over 2 years. When we compared premorbid and baseline data for the three groups, the non-remitted (n = 48), remitted for <6 months (n = 38) and for more than 6 months (n = 207), duration of untreated psychosis (DUP) was the only variable that significantly differentiated the groups (median DUP: 25.5, 14.4 and 6.0 weeks, respectively). Three months univariate predictors of non-remission were being single, longer DUP, core schizophrenia, and less excitative and more negative symptoms at baseline. Two-year predictors were younger age, being single and male, deteriorating premorbid social functioning, longer DUP and core schizophrenia. In multivariate analyses DUP, negative and excitative symptoms predicted non-remission at 3 months, but only DUP predicted at 2 years. CONCLUSION: Long DUP predicted both 3 month and 2-year non-remission rates in first-episode psychosis.

Are multi family groups appropriate for patients with first episode psychosis? A 5-year naturalistic follow-up study.

OBJECTIVE: To compare outcome over 5 years for patients who participated in multi family groups (MFGs) to those who refused or were not offered participation. METHOD: Of 301 first episode psychotic patients aged 15-65 years, 147 participated in MFGs. Outcome was measured by drop-out rates, positive and negative syndrome scale (PANSS) symptom scores, and duration of psychotic episodes during the follow-up period. RESULTS: Multi family group participants had a significantly lower drop-out rates at 5-year follow-up than patients who did not participate. However, the MFG participants had significantly less improvement in PANSS positive and excitative symptoms and had significantly longer duration of psychotic symptoms during the follow-up period. CONCLUSION: Multi family groups appear to increase the chance of retaining patients in a follow-up study, but adjustment of the programme may be necessary with first episode psychosis patients to meet their needs better.

A 2-year follow-up of involuntary admission's influence upon adherence and outcome in first-episode psychosis.

OBJECTIVE: To see, if voluntary admission for treatment in first-episode psychosis results in better adherence to treatment and more favourable outcome than involuntary admission. METHOD: We compared consecutively first-admitted, hospitalised patients from a voluntary (n = 91) with an involuntary (n = 126) group as to psychopathology and functioning using Positive and Negative Syndrome Scale and Global Assessment of Functioning Scales at baseline, after 3 months and at 2 year follow-up. Moreover, duration of supportive psychotherapy, medication and number of hospitalisations during the 2 years were measured. RESULTS: More women than men were admitted involuntarily. Voluntary patients had less psychopathology and better functioning than involuntary patients at baseline. No significant difference as to duration of psychotherapy and medication between groups was found. No significant difference was found as to psychopathology and functioning between voluntarily and involuntarily admitted patients at follow-up. CONCLUSION: Legal admission status per se did not seem to influence treatment adherence and outcome.

Baseline profiles of adolescent vs. adult-onset first-episode psychosis in an early detection program.

OBJECTIVE: Psychotic disorders often start in adolescence. We aim to investigate premorbid and baseline differences characterizing patients with an onset of psychosis in adolescence versus adulthood. METHOD: We compare first-episode, DSM-IV non-affective psychosis with onset before (n = 43) and after (n = 189) 18 years on duration of untreated psychosis (DUP), level of symptoms, suicidal behaviour, and other baseline clinical and demographic characteristics. RESULTS: Adolescent onset patients had poorer premorbid functioning, a longer DUP, higher suicidality, and more depressive symptoms. They also had better cognition, fewer psychotic symptoms, and were more likely to be treated on an out-patient basis. CONCLUSION: Adolescents with first-episode psychosis may have a slower and more silent, i.e. insidious onset, and are at risk of experiencing longer treatment delays than adults. They fit the description of what used to be labeled process (versus reactive) schizophrenia.

Clinical epidemiologic first-episode psychosis: 1-year outcome and predictors.

OBJECTIVE: To describe 1-year outcome in a large clinical epidemiologic sample of first-episode psychosis and its predictors. METHOD: A total of 301 patients with first-episode psychosis from four healthcare sectors in Norway and Denmark receiving common assessments and standardized treatment were evaluated at baseline, at 3 months, and at 1 year. RESULTS: Substantial clinical and social improvements occurred within the first 3 months. At 1-year 66% were in remission, 11% in relapse, and 23% continuously psychotic. Female gender and better premorbid functioning were predictive of less severe negative symptoms. Shorter DUP was predictive for shorter time to remission, stable remission, less severe positive symptoms, and better social functioning. Female gender, better premorbid social functioning and more education also contributed to a better social functioning. CONCLUSION: This first-episode sample, being well treated, may be typical of the early course of schizophrenia in contemporary centers.

Reducing the duration of untreated first-episode psychosis -- effects on baseline social functioning and quality of life.

OBJECTIVE: Long duration of untreated psychosis (DUP) is associated with poorer outcome. The TIPS study demonstrated that DUP can be reduced through early detection (ED). As quality of life (QoL) is associated with DUP it is expected that reduction of DUP leads to better QoL. METHOD: Consecutive first-episode patients with a DSM-IV diagnosis of non-organic, non-affective psychosis were included, 281 patients gave informed consent and 263 completed a full evaluation of QoL. RESULTS: There were no differences in subjective QoL between ED and No-ED groups attributable to reduction in DUP. There were significant bivariate differences in frequency of family and social contacts in favor of the ED group, but multivariate analyses indicated that these differences were based on differences in sample characteristics. CONCLUSION: Deterioration in QoL may precede overt symptom formation. Focus on functional loss in ED educational campaigns may identify risk subjects earlier in the course of the disorder.

Measuring quality of life in first-episode psychosis.

Quality of life (QoL) measures are increasingly recognized as necessary parts of outcome assessments in psychosis. The present paper is a comprehensive study of patients with first-episode psychosis where QoL is measured by the commonly used Lehman Quality of Life Interview (L-QoLI). The aim is to examine if the L-QoLI maintain its original structure when used in a group of patients with first-episode psychosis, and to investigate what determines global subjective QoL with a specific emphasis on premorbid adjustment, duration of untreated psychosis (DUP) and clinical symptoms. The study indicates that the psychometric properties of the L-QoLI do not change significantly when used in first-episode samples. The patients report subjective and objective QoL in the fair to good range, with only a moderate association between the objective and subjective measures. Poor global satisfaction is predicted by being single, abusing drugs, being depressed, having a diagnosis of psychotic affective disorder, having poor premorbid social adjustment and DUP over 10 weeks. The study supports the notion that patients with first-episode psychosis construct QoL in the same way as other groups, and that longer durations of compromised function at this stage produces poor satisfaction with life rather than a downward readjustment of expectations.

Does duration of untreated psychosis bias study samples of first-episode psychosis?

OBJECTIVE: While findings are contradictory, many studies report that long Duration of Untreated Psychosis (DUP) correlates with poorer outcome in first episode psychosis. In an outcome study of first-episode psychosis, we compared the patients who refused to participate in a follow-along with those who consented to estimate the importance of this factor in sample recruitment bias. Our questions were: (i) What is the percentage of refusers? (ii) Are there systematic differences between refusers and consenters on DUP and/or other admission variables? (iii) What is the risk of refusal for different values of DUP? METHOD: In an unselected group of consecutively admitted patients we compared follow-along refusers and consenters on the following admission variables: sex, age, diagnostic group, substance abuse, being in-patient, coming from an early detection site and DUP. We conducted a logistic regression analysis with refusal as the outcome variable. RESULTS: Ninety-three of 397 patients (23%) were refusers. In univariate analyses the only significant difference was found for DUP. The median DUP for consenters was 10 weeks and for refusers 32 weeks. DUP remained significant when all independent variables were controlled for. CONCLUSION: DUP was significantly related to risk for refusal. For tests of the impact of DUP on outcome, this may introduce a type II error bias.

Psychological treatment in pre- and early psychosis.

This article aims to overview a broad range of psychosocial treatments for first-episode psychosis, and for the prodromal phase (or so-called at-risk mental state)--the period preceding the first acute episode (Yung and McGorry, 1996). Firstly, an introduction to the empirically based rationale for early intervention in first-episode psychosis is provided. This is followed by a selective review of individual psychotherapies for early psychosis, which then proceeds to a discussion of family-based interventions for first-episode families and the role of group programs. Next, the role of psychological interventions within the newly emerging indicated preventive approach (Mrazek and Haggerty, 1994) for at-risk mental state is examined before some illustrative case material is presented. It is concluded that integrated psychosocial interventions for first-episode psychosis and for prodrome are newly emerging, innovative fields that offer some preventive opportunities. These opportunities, combined with some initial outcome data, warrant continuing research and clinical innovation.

Methodological pitfalls in early detection studies - the NAPE Lecture 2002. Nordic Association for Psychiatric Epidemiology.

OBJECTIVE: To identify and discuss methodological pitfalls that may help explain why many questions around early detection (ED) and duration of untreated psychosis (DUP) are still unsolved. METHOD: This paper concentrates on pitfalls in the following areas: sampling, measurement and data analyses. RESULTS: The main problems seem to be: SAMPLING: Referral bias, exclusion of patients, patient refusal, and patients lost to follow-up. MEASUREMENT: Reliability, which is particularly cogent for multisite investigations, and validity, which includes: Start of illness, start of psychosis, diagnoses, start of treatment, the relationship between ED and DUP and choice of outcome measures. Data Analyses: Overlooking threshold effects of DUP, improper control for baseline scores, and lack of control for confounders. CONCLUSION: Methodological pitfalls may bias ED studies. Several pitfalls are unavoidable, but proper design and quality assurance can reduce their impact. Researchers ought to identify the pitfalls, and to estimate and discuss their influence.