Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness.

BACKGROUND: Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation. METHODS: We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV. RESULTS: We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males. CONCLUSION: We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. METHODS: We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. RESULTS: We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. CONCLUSIONS: Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

Bidirectionality of antiseizure and antipsychotic treatment: A population-based study.

PURPOSE: To study the prevalence and directionality of comorbid epilepsy and psychosis in Norway. METHODS: The Norwegian Prescription Database (NorPD) provided individual-based information on all antiseizure medications (ASMs) and antipsychotic drugs (APDs) dispensed during 2004-2017. Subjects were ≥18 years of age at the end of the study period. Diagnosis-specific reimbursement codes from the 10th revision of the International Classification of Diseases/2nd edition of the International Classification of Primary Care (ICD-10/ICPC-2) combined with ATC codes were used as indicators of diagnosis. Subjects had collected ASMs for epilepsy or APDs for psychosis at least four times, at least once issued with an ICD-10 code from the specialist healthcare service. Directionality was analyzed in subjects receiving both treatments. To reduce prevalent comorbidity bias, we employed a four-year comorbidity-free period (2004-2007). The use of specific ASMs and APDs was analyzed. RESULTS: A total of 31,289 subjects had collected an ASM for epilepsy at least four times, 28,889 an APD for psychosis. Both the prevalence of treatment for epilepsy and of treatment for psychosis was 0.8%. Further, 891 subjects had been treated for both conditions; 2.8% with epilepsy had been treated for psychosis, and 3.1% with psychosis had been treated for epilepsy. Among 558 subjects included in the analyses of directionality, 56% had collected the first APD before an ASM, whereas 41% had collected an ASM first. During the last year prior to comorbidity onset, levetiracetam, topiramate, or zonisamide had been used for epilepsy by approximately 40%, whereas olanzapine and quetiapine were most used in patients with psychosis, and clozapine in 13%. CONCLUSION: The proportion of patients with prior antipsychotic treatment at onset of epilepsy is higher than previously acknowledged, as demonstrated in this nation-wide study. Apart from a shared neurobiological susceptibility, the bidirectionality of epilepsy and psychosis may be influenced by various environmental factors, including the interaction of pharmacodynamic effects. APDs may facilitate seizures; ASMs may induce psychiatric symptoms. In patients with combined treatment, these potential drug effects should receive ample attention, along with the psychosocial consequences of the disorders. A prudent multi-professional approach is required.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Strength training restores force-generating capacity in patients with schizophrenia.

Patients with schizophrenia spectrum disorders have impaired skeletal muscle force-generating capacity (FGC) of the lower extremities, that is, one repetition maximum (1RM) and rapid force development, and poor functional performance. We therefore investigated whether 12 weeks of maximal strength training (MST) could (a) restore FGC and functional performance to the level of healthy references, (b) increase patient activation and quality of life, and (c) explore associations between symptom severity, defined daily dose of medication, illness duration, level of patient activation, and improvements in FGC and functional performance. Forty-eight outpatients were randomized to a training group (TG) or control group (CG). TG performed leg press MST 2 day/week at ~ 90% 1RM. The CG received two introductory training sessions and encouragement to train independently. Leg press 1RM, rapid force development, a battery of functional performance tests, Patient Activation Measure-13, and 36-Item Short Form Health Survey were tested. Healthy references performed baseline tests of FGC and functional performance. Thirty-six patients completed the study (TG: 17, CG: 19). TG improved 1RM (28%) and rapid force development (20%, both P < .01) to a level similar to healthy references, while no change was apparent in the CG. TG's improvement in rapid force development was negatively associated with defined daily dose of medication (r = -0.5, P = .05). Both TG and CG improved 30-second sit-to-stand test performance (P < .05) which was associated with improved rapid force development (r = 0.6, P < .05). In conclusion, 12 weeks of MST restored patients' lower extremity FGC to a level similar to healthy references and improved 30-second sit-to-stand test performance.

Mid-Pregnancy Insomnia and its Association with Perinatal Depressive Symptoms: A Prospective Cohort Study.

Objective/Background: Insomnia and depression are disorders that affect many perinatal women and that often are interrelated. The present study aimed to examine concurrent and prospective associations between mid-pregnancy insomnia and depression during mid-pregnancy and 8 weeks postpartum. Furthermore, differences in depression and in the sleep-related characteristics insomnia, chronotype, and sleep efficiency were explored between the two time points (mid-pregnancy versus 8 weeks postpartum), and between primiparous and multiparous participants.Participants/Methods: The study was part of the Norwegian population-based Depression and Anxiety in the Perinatal Period (DAPP) prospective cohort study. Among 539 women that were recruited for participation when receiving a routine ultrasound examination, we analyzed data from hospital birth records and questionnaire responses from pregnancy week 17 and postpartum week 8. We used the Edinburgh Postnatal Depression Scale to measure depression. The Bergen Insomnia Scale, the reduced Horne-Östberg Morningness-Eveningness Questionnaire, and three questions from the Pittsburgh Sleep Quality Index were used to measure the sleep-related characteristics.Results: Mid-pregnancy insomnia was significantly associated with concurrent depression (p < .001), but not with postpartum depression (p = .288), in a linear mixed model with adjustment for several reproductive and psychosocial variables. Sleep efficiency was reduced from mid-pregnancy to postpartum (from 88% to 77%), and primiparous women reported less efficient sleep than multiparous women after childbirth.Conclusions: The results indicate that mid-pregnancy insomnia may be a marker for concurrent depression but not a predictor of postpartum depression. Future research should examine the extent to which treatment of insomnia from mid-pregnancy on reduces both perinatal insomnia and depression.

One-year aerobic interval training in outpatients with schizophrenia: A randomized controlled trial.

Although aerobic interval training (AIT) is recognized to attenuate the risk of cardiovascular disease (CVD) and premature mortality, it appears that it rarely arrives at patients' doorsteps. Thus, this study investigated 1-year effects and feasibility of AIT delivered with adherence support in collaborative care of outpatients with schizophrenia. Forty-eight outpatients (28 men, 35 [31-38] (mean [95% confidence intervals]) years; 20 women, 36 [30-41] years) with schizophrenia spectrum disorders (ICD-10) were randomized to either a collaborative care group provided with municipal transportation service and training supervision (walking/running 4 × 4 minutes at ~90% of peak heart rate; HRpeak ) 2 d wk-1 at the clinic (TG) or a control group (CG) given 2 introductory AIT sessions and advised to continue training. Directly assessed peak oxygen uptake ( V ˙ O 2 peak ) increased in the TG after 3 months (2.3 [0.6-4.4] mL kg-1  min-1 , Cohen's d = 0.33[-4.63 to 4.30], P = 0.04), 6 months (2.7 [0.5-4.8] mL kg-1  min-1 , Cohen's d = 0.42[-4.73 to 4.11], P = 0.02) and 1 year (4.6 [2.3-6.8] mL kg-1  min-1 , Cohen's d = 0.70[-4.31 to 4.10], P < 0.001) compared to the CG. One-year cardiac effects revealed higher HRpeak (7 [2-11] b min-1 , Cohen's d = 0.34[-8.48 to 8.65], P = 0.01), while peak stroke volume tended to be higher (0.9 [-0.2 to 2.0] mL b-1 , Cohen's d = 0.35[-1.62 to 2.01], P = 0.11) in the TG compared to the CG. Conventional risk factors (body weight, waist circumference, blood pressure, and lipids/glucose) remained unaltered in both groups. One-year AIT adherence rates were 15/25 (TG; different from CG: P < 0.001) and 0/23 (CG). AIT was successfully included in long-term collaborative care of outpatients with schizophrenia and yielded improved V ˙ O 2 peak , advocating this model for aerobic capacity improvement and CVD risk reduction in future treatment.

Inflammatory markers are altered in severe mental disorders independent of comorbid cardiometabolic disease risk factors.

BACKGROUND: Inflammation and immune activation have been implicated in the pathogenesis of severe mental disorders and cardiovascular disease (CVD). Despite high level of comorbidity, many studies of the immune system in severe mental disorders have not systematically taken cardiometabolic risk factors into account. METHODS: We investigated if inflammatory markers were increased in schizophrenia (SCZ) and affective (AFF) disorders independently of comorbid CVD risk factors. Cardiometabolic risk factors (blood lipids, body mass index and glucose) and CVD-related inflammatory markers CXCL16, soluble interleukin-2 receptor (sIL-2R), soluble CD14 (sCD14), macrophage inhibitory factor and activated leukocyte cell adhesion molecule (ALCAM) were measured in n = 992 patients (SCZ, AFF), and n = 647 healthy controls. We analyzed the inflammatory markers before and after controlling for comorbid cardiometabolic risk factors, and tested for association with psychotropic medication and symptom levels. RESULTS: CXCL16 (p = 0.03) and sIL-2R (p = 7.8 × 10-5) were higher, while sCD14 (p = 0.05) were lower in patients compared to controls after controlling for confounders, with significant differences in SCZ for CXCL16 (p = 0.04) and sIL-2R (p = 1.1 × 10-5). After adjustment for cardiometabolic risk factors higher levels of sIL-2R (p = 0.001) and lower sCD14 (p = 0.002) remained, also in SCZ (sIL-2R, p = 3.0 × 10-4 and sCD14, p = 0.01). The adjustment revealed lower ALCAM levels (p = 0.03) in patients. We found no significant associations with psychotropic medication or symptom levels. CONCLUSION: The results indicate that inflammation, in particular enhanced T cell activation and impaired monocyte activation, are associated with severe mental disorders independent of comorbid cardiometabolic risk factors. This suggests a role of novel pathophysiological mechanisms in severe mental disorders, particularly SCZ.

Patients with schizophrenia have impaired muscle force-generating capacity and functional performance.

Patients with schizophrenia have impaired physical health. However, evidence of how skeletal muscle force-generating capacity (FGC), a key component of functional performance, may contribute to the impairment is scarce. Thus, the aim of this study was to investigate the patient groups' skeletal muscle FGC and its association with functional performance. Leg-press FGC was assessed along with a battery of functional performance tests in 48 outpatients (28 men, 34 ± 10 years; 20 women, 36 ± 12 years) with schizophrenia spectrum disorder (ICD-10, F20-29), and compared with 48 healthy age- and gender-matched references. Results revealed reduced one-repetition maximum (1RM) in men (-19%, P < .01) and a trend toward reduction in women (-13%, P = .067). The ability to develop force rapidly was also impaired (men: -30%; women: -25%, both P < .01). Patients scored worse than healthy references on all physical performance tests (stair climbing: -63%; 30-second sit-to-stand (30sSTS): -48%; six-minute walk test (6MWT): -22%; walking efficiency: -14%; and unipedal stance eyes open: -20% and closed: -73%, all P < .01). 1RM correlated with 6MWT (r = .45), stair climbing (r = -.44), 30sSTS (r = .43), walking efficiency (r = .26), and stance eyes open (r = .33) and closed (r = .45), all P < .01. Rapid force development correlated with 6MWT (r = .54), stair climbing (r = -.49), 30sSTS (r = .45), walking efficiency (r = .26), and stance eyes open (r = .44) and closed (r = .51), all P < .01. In conclusion, skeletal muscle FGC and functional performance are reduced in patients with schizophrenia and should be recognized as important aspects of the patient groups' impaired health. Resistance training aiming to improve these components should be considered an important part of clinical treatment.

A comprehensive cardiovascular disease risk profile in patients with schizophrenia.

Patients with schizophrenia are physically inactive and have high prevalence of cardiovascular disease (CVD). Peak oxygen uptake (V̇O2peak ) is one of the strongest predictors for CVD, yet is rarely investigated in this patient population, and how V̇O2peak relates to other conventional CVD risk measures in this population is unclear. We measured treadmill V̇O2peak along with daily physical activity assessed by triaxial accelerometry, body mass index (BMI), waist circumference, blood pressure, lipid profiles, and glucose in 48 outpatients (28 men, 35 ± 10 (SD) years; 20 women, 35 ± 12 years), diagnosed with schizophrenia, schizotypal, or delusional disorders (ICD-10; F20-29). The patients were compared with 48 age- and sex-matched healthy references (±2 years) and normative data from the population. V̇O2peak was 34.5 ± 8.7 mL/kg/min (men) and 26.4 ± 7.0 mL/kg/min (women), which was 27% and 30% lower than healthy references, respectively (both P < 0.01). V̇O2peak was not associated with daily physical activity in men while a weak association was seen in women (steps per day: r2  = 0.26; counts per minute: r2  = 0.25; P < 0.05). BMI (26.0 ± 6.1 kg/m2 ) revealed that patients were moderately overweight with a waist circumference of 103 ± 17 cm. Lipid- and glucose levels, and blood pressure were all within normative range. Our data advocate the utilization of V̇O2peak assessment for CVD risk profile determination in patients with schizophrenia. Daily physical activity was poorly and inconsistently related to V̇O2peak, suggesting increased daily physical activity might not translate into improved V̇O2peak and CVD risk reduction.

Right unilateral electroconvulsive therapy does not cause more cognitive impairment than pharmacologic treatment in treatment-resistant bipolar depression: A 6-month randomized controlled trial follow-up study.

OBJECTIVES: Electroconvulsive therapy is an effective treatment for bipolar depression, but there are concerns about whether it causes long-term neurocognitive impairment. METHODS: In this multicenter randomized controlled trial, in-patients with treatment-resistant bipolar depression were randomized to either algorithm-based pharmacologic treatment or right unilateral electroconvulsive therapy. After the 6-week treatment period, all of the patients received maintenance pharmacotherapy as recommended by their clinician guided by a relevant treatment algorithm. Patients were assessed at baseline and at 6 months. Neurocognitive functions were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and autobiographical memory consistency was assessed using the Autobiographical Memory Interview-Short Form. RESULTS: Seventy-three patients entered the trial, of whom 51 and 26 completed neurocognitive assessments at baseline and 6 months, respectively. The MATRICS Consensus Cognitive Battery composite score improved by 4.1 points in both groups (P = .042) from baseline to 6 months (from 40.8 to 44.9 and from 41.9 to 46.0 in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively). The Autobiographical Memory Interview-Short Form consistency scores were reduced in both groups (72.3% vs 64.3% in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively; P = .085). CONCLUSIONS: This study did not find that right unilateral electroconvulsive therapy caused long-term impairment in neurocognitive functions compared to algorithm-based pharmacologic treatment in bipolar depression as measured using standard neuropsychological tests, but due to the low number of patients in the study the results should be interpreted with caution. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00664976.

Predictors of long term use of psychiatric services of patients with recent-onset schizophrenia: 12 years follow-up.

BACKGROUND: The aim of study was to investigate predictors of long term use of psychiatric services of patients with recent-onset schizophrenia. METHODS: A cohort of 50 clinically stable patients with recent-onset schizophrenia was included in a randomized controlled trial comparing early integrated treatment with treatment as usual. Recent onset was defined as emergence of psychotic symptoms for the first time during the preceding 2 years. The follow up period was from the date of randomization and until 12 years after termination of treatment trial, 14 years forward. RESULTS: Score on Brief psychiatric rating scale both at baseline and after 2 years of treatment, suicide attempts during 2 years of treatment and being an inpatient during 2 years of treatment were significant predictors of long term use of services. CONCLUSION: High score on Brief psychiatric rating scale, suicide attempts and being admitted as inpatient early in the course of schizophrenia are possible predictors of long term use of services. TRIAL REGISTRATION: ClinicalTrials.gov NCT00184509 . Registered 15 September 2005.

Variability of activity patterns across mood disorders and time of day.

BACKGROUND: Few actigraphy studies in mood disorders have simultaneously included unipolar (UP) and bipolar (BD) depression or BD mixed states as a separate subgroup from mania. This study compared objectively measured activity in UP, BD depression, mania and mixed states and examined if patterns differed according to time of day and/or diagnostic group. METHODS: Eighty -eight acutely admitted inpatients with mood disorders (52 UP; 18 mania; 12 BD depression; 6 mixed states) underwent 24 hours of actigraphy monitoring. Non-parametric analyses were used to compare median activity level over 24 h (counts per minute), two time series (64-min periods of continuous motor activity) in the morning and evening, and variability in activity across and within groups. RESULTS: There was no between-group difference in 24-h median level of activity, but significant differences emerged between BD depression compared to mania in the active morning period, and between UP and mania and mixed states in the active evening period. Within-group analyses revealed that UP cases showed several significant changes between morning and evening activity, with fewer changes in the BD groups. CONCLUSIONS: Mean activity over 24 hours has limited utility in differentiating UP and BD. In contrast, analysis of non-linear variability measures of activity at different times of day could help objectively distinguish between mood disorder subgroups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01415323 , first registration July 6, 2011.

A randomized controlled trial comparing self-referral to inpatient treatment and treatment as usual in patients with severe mental disorders.

BACKGROUND: There has been a call for increased patient autonomy and participation in psychiatry. Some Community Mental Health Centres (CMHC) have implemented services called 'self-referral to inpatient treatment' (SRIT) for patients with severe mental disorders. AIMS: To investigate whether SRIT could yield better outcomes after 12 months in use of mental health services for people with severe mental disorders than Treatment As Usual (TAU). METHODS: This was a randomized controlled trial at a CMHC in Norway comparing SRIT and TAU in 12 months. Fifty-four patients with severe mental disorders were included. The patients in the SRIT group could admit themselves as inpatients for up to 5 days for each admission with at least a 2 weeks pause between the admittances. RESULTS: Twenty out of 26 participants (77%) in the SRIT group used the SRIT for a median of 1.5 admissions and 5 inpatient days. With the exception of a somewhat larger number of admissions at the CMHC in the SRIT group, no significant differences were found between the two groups in days as inpatients, admissions, outpatient contacts or coercion. Both groups reduced their inpatients days by 40%. CONCLUSIONS: Both the SRIT and the TAU groups reduced their use of services during the 12 months intervention period. Giving patients with severe mental disorders the possibility to self-refer did not change the use of services. CLINICAL IMPLICATIONS: Self-referral to inpatient treatment for patients with severe mental disorders might increase patient autonomy, but does not seem to save use of inpatient services.

Paroxetine, Cognitive Therapy or Their Combination in the Treatment of Social Anxiety Disorder with and without Avoidant Personality Disorder: A Randomized Clinical Trial.

BACKGROUND: The most efficacious treatments for social anxiety disorder (SAD) are the SSRIs and cognitive therapy (CT). Combined treatment is advocated for SAD but has not been evaluated in randomized trials using CT and SSRI. Our aim was to evaluate whether one treatment is more effective than the other and whether combined treatment is more effective than the single treatments. METHODS: A total of 102 patients were randomly assigned to paroxetine, CT, the combination of CT and paroxetine, or pill placebo. The medication treatment lasted 26 weeks. Of the 102 patients, 54% fulfilled the criteria for an additional diagnosis of avoidant personality disorder. Outcomes were measured at posttreatment and 12-month follow-up assessments. RESULTS: CT was superior to paroxetine alone and to pill placebo at the end of treatment, but it was not superior to the combination treatment. At the 12-month follow-up, the CT group maintained benefits and was significantly better than placebo and paroxetine alone, whereas there were no significant differences among combination treatment, paroxetine alone, and placebo. Recovery rates at 12 months were much higher in the CT group (68%) compared to 40% in the combination group, 24% in the paroxetine group, and 4% in the pill placebo group. CONCLUSIONS: CT was the most effective treatment for SAD at both posttreatment and follow-up compared to paroxetine and better than combined treatment at the 12-month follow-up on the Liebowitz Social Anxiety Scale. Combined treatment provided no advantage over single treatments; rather there was less effect of the combined treatment compared to CT alone.

The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.

BACKGROUND: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. METHODS/DESIGN: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. DISCUSSION: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.

Analyzing Seasonal Variations in Suicide With Fourier Poisson Time-Series Regression: A Registry-Based Study From Norway, 1969-2007.

Seasonal variation in the number of suicides has long been acknowledged. It has been suggested that this seasonality has declined in recent years, but studies have generally used statistical methods incapable of confirming this. We examined all suicides occurring in Norway during 1969-2007 (more than 20,000 suicides in total) to establish whether seasonality decreased over time. Fitting of additive Fourier Poisson time-series regression models allowed for formal testing of a possible linear decrease in seasonality, or a reduction at a specific point in time, while adjusting for a possible smooth nonlinear long-term change without having to categorize time into discrete yearly units. The models were compared using Akaike's Information Criterion and analysis of variance. A model with a seasonal pattern was significantly superior to a model without one. There was a reduction in seasonality during the period. Both the model assuming a linear decrease in seasonality and the model assuming a change at a specific point in time were both superior to a model assuming constant seasonality, thus confirming by formal statistical testing that the magnitude of the seasonality in suicides has diminished. The additive Fourier Poisson time-series regression model would also be useful for studying other temporal phenomena with seasonal components.

Religious convictions in patients with epilepsy-associated affective disorders: a controlled study from a psychiatric acute department.

Patients with epilepsy often have different mood symptoms and behavioral trait characteristics compared to the non-epileptic population. In the present prospective study, we aimed to assess differences in behavioral trait characteristics between acutely admitted, psychiatric in-patients with epilepsy-associated depressive symptoms and gender/age-matched patients with major depression. Patients with epilepsy-associated depression had significantly higher scores for "religious convictions," "philosophical and intellectual interests" and "sense of personal destiny." These behavioral trait characteristics at admission or in clinical history should alert the psychiatrist and lead to closer examination for a possible convulsive disorder.