Persistent tachycardia in clozapine treated patients: A 24-hour ambulatory electrocardiogram study.

Tachycardia is associated with cardiovascular mortality. Tachycardia is also a known clozapine adverse effect. However, whether clozapine-associated tachycardia is persistent is not known. Thirty clozapine-treated patients with clinical tachycardia were investigated with 24-hour ambulatory electrocardiography (ECG). Baseline peripheral heart rate (HR) was 106.7±7.8. The ambulatory ECG 24-hour-HR was 98.7±9.7. Baseline HR and 24-hour-HR correlated strongly (r=0.74, p=0.000003). Daytime HR was 106.4±9.9 and nighttime HR 89.2±12.0. Low dose bisoprolol reduced HR significantly. The high 24-hour-HR indicates a persistent tachycardia. Tachycardia should not discourage from clozapine use but the findings indicate a need of guidelines for detection and treatment of clozapine-associated tachycardia.

Tachycardia in patients treated with clozapine versus antipsychotic long-acting injections.

Tachycardia is a known adverse effect during clozapine treatment. However, prevalence reported differs widely between studies and hitherto there are no studies comparing clozapine-treated patients with a similar control group. The present study was carried out to assess the prevalence of tachycardia in patients treated with clozapine and antipsychotic long-acting injections (LAI). Data on heart rate (HR), concomitant medication, and relevant anthropometric and laboratory measurements were collected for all clozapine-treated patients (n=174) in a defined catchment area and compared with data on patients treated with LAI (n=87). In total, 33% of patients on long-term clozapine treatment had tachycardia (HR>100) compared with 16% in the LAI group (P<0.001). The mean HR was 91 in the clozapine group and 82 in the LAI group (P<0.001). Clozapine dose correlated with HR. The majority of patients with HR more than 100 received no specific treatment for tachycardia. In conclusion, the prevalence of tachycardia was twice as high in patients treated with clozapine as in a similar patient group with severe schizophrenia spectrum disorder. The tachycardia was in many cases clinically unnoticed. Tachycardia during antipsychotic treatment is a common phenomenon that must be monitored for actively and, when noticed, further investigated and treated.

Maintenance therapy with second generation antipsychotics for bipolar disorder - A systematic review and meta-analysis.

BACKGROUND: Second generations antipsychotics (SGA) are frequently used for maintenance treatment in bipolar disorder. We systematically reviewed the efficacy and long-term effects of treatment with SGA, regardless of treatment strategy (SGA administered either as monotherapy or as adjunctive therapy), in comparison to placebo, lithium or valproate. Primary outcomes were relapses (mood episode recurrence) and discontinuation. METHOD: Clinical studies were identified through database searching in PubMed, Embase, PsychInfo and Cochrane Library and critically appraised based on the Cochrane Handbook. Full data extraction of raw data was performed and analyzed with meta-analyses, and level of evidence graded using GRADE. Only randomized controlled studies (RCT) and observational studies were included, with a minimum follow-up of 6 months. Comparators used were restricted to placebo, lithium, valproate or other anti-epileptic drugs. RESULTS: We identified 15 RCTs on SGA in bipolar disorder with follow-up-time of 6 months up to 2 years, and one observational study reporting long-term effects of up to 4 years. A total of 6142 patients were included in the randomized trials. No long-term RCTs beyond 2 years follow-up was identified. All RCTs except for one included patients with bipolar disorder type I only. All RCTs except for two included patients pre-stabilized on the drug under investigation prior to randomization (enrichment design). For SGA as adjunctive therapy to lithium or valproate, meta-analyses showed that treatment with either aripiprazole (RR: 0.65, 95% CI 0.50-0.85), quetiapine (RR: 0.38, 95% CI 0.32-0.46) or ziprasidone (RR: 0.62, 95% CI 0.40-0.96) reduced the overall risk of relapses in patients that had responded during the stabilization phase. Adjunctive therapy with quetiapine was the only drug that reduced both manic and depressive episodes. For SGA as monotherapy, only quetiapine was shown to be better than lithium/ valproate for both manic and depressive relapses, but only for patients stabilized on quetiapine during the acute phase. As monotherapy, olanzapine, quetiapine and risperidone were shown to be superior to placebo in reducing the overall risk of relapses. LIMITATIONS: There were considerable limitations to the evidence base of maintenance treatment with SGA in bipolar disorder. Most studies used stabilized patients, i.e. enrichment design (selection bias), had considerable dropout levels (attrition bias), and variable degree of reporting bias. No long-term RCT data on efficacy is available beyond 2 years, and almost all studies are on bipolar disorder type I patients only. Despite these limitations, we elucidate quantitative findings from meta-analyses conducted on the randomized trials published on the topic.

Risk factors for suicide among patients with schizophrenia: a cohort study focused on cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid.

BACKGROUND: The objective of this study was to investigate the association between 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF), bullying, and later suicide among patients with schizophrenia. METHODS: Ninety-nine patients with schizophrenia were included. Correlations of clinical factors, 5-HIAA and HVA, and later suicide were investigated. RESULTS: Twelve patients committed suicide (12%) during a 28-year follow-up period. Later suicide was correlated to bullying in childhood (P=0.02) and a lower quotient of HVA/5-HIAA in CSF (P<0.05). CONCLUSION: Suicide in schizophrenia is related to childhood exposedness and CSF neurotransmitter levels.

Neuropeptide Y, social function and long-term outcome in schizophrenia.

There is a lack of biomarkers in schizophrenia and the mechanisms underlying the observed deficits in social functioning are poorly understood. This cohort study aimed to explore whether neurotransmitter neuropeptide Y (NPY) in cerebrospinal fluid (CSF) from patients with schizophrenia is correlated to social function and clinical variables. A further aim was to determine whether baseline levels of NPY were associated with subsequent 3-year outcome. Fifty-six consecutively admitted patients with schizophrenia were included and underwent lumbar puncture and symptom ratings before antipsychotic treatment. NPY levels in CSF were determined by radioimmunoassay. Social function (Social Competence and Social Interest) was assessed by Nurses' Observation Scale for Inpatient Evaluation while psychiatric symptoms were rated using the Comprehensive Psychopathological Rating Scale. Three-year outcome was assessed with the Strauss-Carpenter Outcome Scale. Cross-sectional analysis showed a correlation between level of NPY and Social Competence at index admission (r(s)=0.37, p<0.05). The longitudinal analysis (i.e., at the 3-year follow-up) indicated that, for each standard deviation increase in baseline NPY, there was an increased risk of being unemployed (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.07-3.82), having moderate or severe symptoms (OR 3.09, CI 1.30-7.32) or being hospitalized at least 6 months the previous year (OR 3.24, CI 1.09-9.64). However, NPY was not correlated to Social Interest or clinical variables at index admission. In conclusion, NPY levels in CSF are correlated to Social Competence and seem to predict some aspects of longitudinal outcome in schizophrenia.

Electrocardiographic signs of autonomic imbalance in medicated patients with first-episode schizophrenia spectrum disorders--relations to first treatment discontinuation and five-year remission status.

PURPOSE: To explore measures in electrocardiograms (ECG) influenced by autonomic balance in early schizophrenia spectrum disorders and to examine their relation to subsequent first antipsychotic pharmacotherapy discontinuation and five-year remission status. SUBJECTS AND METHODS: Twelve-lead ECGs were recorded at baseline in 58 patients with first-episode schizophrenia spectrum disorders and in 47 healthy controls of similar age. Selected ECG variables included heart rate and measures of repolarization. Pharmacotherapy data were extracted from medical records. At a five-year follow-up the patients were interviewed and assessed with the positive and negative syndrome scale. RESULTS: Patients had higher heart rate and a different ST-T pattern than the controls. High T-wave amplitudes in the leads aVF and V5 and ST-elevations in V5 were associated both with higher risk of an earlier discontinuation of first antipsychotic pharmacotherapy and with non-remission five years later. DISCUSSION AND CONCLUSION: In this longitudinal cohort study, simple ECG measures influenced by autonomic balance in the early phase of schizophrenia spectrum disorders contained prognostic information. As this is the first report of this association and is based on a relatively small sample, the results should be interpreted with caution.

Improved cognitive functions after treatment with an oral appliance in obstructive sleep apnea.

OBJECTIVE: The objective of this study was to evaluate the effect of oral appliance (OA) treatment on cognitive functions in patients with obstructive sleep apnea (OSA). MATERIALS AND METHODS: In a prospective study, 50 male patients with verified moderate-to-severe OSA received an OA with mandibular advancement. The cognitive functions assessed included working memory, vigilance, executive functioning, and mental pace, measured before as well as after 6 months of treatment. Somnography was used to measure physiological treatment effects. Forty-three patients completed the 6-month follow-up study. RESULTS: All domains of cognitive functioning measured improved after 6 months of treatment with an OA (P <; 0.001). The apnea/hypopnea- and oxygen desaturation-indices decreased significantly after treatment (P <; 0.01). An obvious treatment response was reached in 60% of the patients, and 54% of the patients had recovered ie, had normalized breathing during sleep. CONCLUSION: OA with mandibular advancement is a treatment modality for the physiological symptoms of OSA, and may have a positive impact on cognitive functions, after only 6 months of treatment.

Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder.

BACKGROUND: Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA). This astrocyte-derived mediator acts as a neuroprotectant and modulates sensory gating and cognitive function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder. METHODS: We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high-performance liquid chromatography. RESULTS: Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean [SEM] 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers. LIMITATIONS: The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease. CONCLUSION: Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disorder.

The self-assessment Global Quality of Life scale: Reliability and construct validity.

Abstract Objective. The aim was to establish psychometric properties of the Global Quality of Life Scale (GQL) for people with severe mental illness. Methods. GQL is a stand-alone visual analogue scale included in "The Quality Star", a minimal platform for clinical follow-up and efficiency documentation of mental health services in eight dimensions widely used in Sweden. Validating instruments included MANSA, Inventory of Problem and Solutions, Consumer Satisfaction Rating Scale, Perceived Global Distress, health screening using UKU-Side Effect Rating Scale, GAF, and Perceived Global Burden (for next of kin). Test-retest reliability of the GQL was examined between ratings at quarterly intervals during 1 year. Results. There were three main results: test-retest reliability at quarterly intervals was very satisfactory, concurrent validity with the initial item of life satisfaction scale of MANSA, "Life as a whole", was demonstrated and finally content validity was clarified by associations with a number of validating measures from several contexts in three studies. Conclusion. GQL have acceptable psychometric properties and is valid for serious mental ill persons. Its use as easy-to-use instrument for screening of perceived global quality of life was supported.

Five-year outcome of first-episode psychosis before and after the implementation of a modified assertive community treatment programme.

OBJECTIVE: Assertive community treatment programmes are increasingly common worldwide but without much knowledge of their long-term effect. We investigated whether the implementation of such a programme would improve symptomatic and functional outcome 5 years later. METHODS: Naturalistic cohort study between 1995 and 2000 of all first-episode psychosis patients (n = 144) in Uppsala County, Sweden. We compared a 3-year period before (non-mACT) and after the introduction of a modified assertive community treatment (mACT) programme in 1998. Five-year outcome was assessed for symptoms and functioning and the two co-primary outcome measures were positive and negative symptoms. Regression models were adjusted for a propensity score based on multiple baseline variables and use of antipsychotics at 5-year follow-up. RESULTS: Contrary to our hypothesis, patients in the mACT group, compared to those in the non-mACT group, had a borderline significant increased risk of having a poor 5-year outcome regarding positive psychotic symptoms [adjusted odds ratio (OR) 3.21, 95% confidence interval (CI) 0.97-10.63]. There was no difference at the 5-year follow-up between the mACT and non-mACT group regarding negative symptoms (adjusted OR 1.65, 95% CI 0.48-5.66), or any of the secondary outcome measures: global assessment of functioning, hazardous alcohol use, use of illicit drugs, working or being in education, independent living, subjective satisfaction with life or suicide. Results were similar in subgroup analyses. CONCLUSIONS: The implementation of a modified assertive community treatment was not followed by subsequent improvements of 5-year outcome on a group level for patients with first-episode psychosis.

Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders.

BACKGROUND: Patients with psychotic symptoms often respond poorly to treatment. Outcomes can be affected by biological, physiological and psychological factors according to the vulnerability-stress model. The patient's coping strategies and beliefs have been correlated with outcomes. OBJECTIVES: To investigate the knowledge and insight in relation to treatment response. METHODS: A naturalistic study was performed using patient interviews and information gathered from patient drug charts. Apart from the rating scales used for classification of treatment response (CANSEPT method), the SPKS knowledge of illness and drugs rating scale was utilized. RESULTS: In the group of patients in functional remission (FR; n = 38), 37% had insight into their illness as compared to 10% among those not in functional remission (non-FR; n = 78; P < 0.01). As much as 23% of the non-FR group had no strategy for responding to warning signs versus 8% in the FR group (P < 0.05). CONCLUSIONS: Better treatment outcomes appear to be associated with better insight into illness, higher knowledge of warning signs and better coping strategies.

Biochemical risk factors for development of obesity in first-episode schizophrenia.

Obesity is a serious health issue for many patients with schizophrenia. There is a lack of predictors for and understanding of the development of obesity in the early phase of the illness. Therefore we investigated a set of routine biochemistry variables in blood as predictors of the development of obesity and weight gain over 5 years in an observational cohort study of patients with first-episode schizophrenia (n=59). Twelve percent of the patients were obese at baseline and 37% were obese at the 5-year follow-up. The mean body mass index (BMI) change over 5 years was a 4.1 kg/m(2) increase (4.5 SD). Obesity was predicted by baseline hemoglobin levels (odds ratio per standard deviation [OR/SD] 3.3, 95% confidence interval [CI] 1.4 to 7.5), red blood cell count (OR/SD 2.6, 95% CI 1.2 to 5.5), hematocrit (OR/SD 2.8, 95% CI 1.3 to 5.9), gamma-glutamyltransferase (OR/SD 2.8, 95% CI 1.2-6.3) and creatinine (OR/SD 3.1, 95% CI 1.2 to 8.0). After adjustment for baseline BMI, the associations were attenuated for gamma-glutamyltransferase and creatinine. Low baseline BMI was associated with a greater BMI increase. The major conclusion is that easily available routine biochemistry markers can be useful in predicting the development of obesity in first-episode schizophrenia. The mechanisms underlying the observed associations are unknown, but the predictors identified in this study could signify dehydration or insulin resistance. These observations open a new window to future research on the mechanisms underlying the development of obesity in schizophrenia.

Treatment response in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission.

BACKGROUND: Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. CONCLUSION: In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

Association between symptomatic remission and functional outcome in first-episode schizophrenia.

Although operational criteria for remission in schizophrenia have recently been proposed, the association of this definition with broader functional outcome has not yet been established in first-episode patients. The severity criteria for remission consist of a score of mild or less on eight core symptoms of schizophrenia. We applied the severity criteria for remission to a sample of patients with first-episode schizophrenia (n=76) in order to explore the association with functional outcome five years after first presentation to mental healthcare. We evaluated whether other factors than those included in the remission definition predicted good function in logistic regression models. The discriminatory capacities for remission and other factors for good function were tested using C-statistics. The proportions of remitters and non-remitters having good function were 73% and 17%, respectively. Furthermore, remitters had a higher level of subjective satisfaction with life. In comparison with non-remission, symptomatic remission was strongly associated with good function: odds ratio 13.2, 95% confidence interval, 4.3 to 40.3. A duration of untreated psychosis of three months or less as compared with a longer duration was associated with having good function at a five-year follow-up independently of remission status. The discriminatory capacity for symptomatic remission between having good function vs. not was acceptable (C-statistic=0.78), which was significantly improved to an excellent discriminatory capacity by adding duration of untreated psychosis less than three months (C-statistic=0.83, p=0.04). In conclusion, core symptoms of schizophrenia have an important limiting effect on functioning and subjective life satisfaction in the early course of the illness.

Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting.

RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

The monoamine oxidase A (MAO-A) gene, family function and maltreatment as predictors of destructive behaviour during male adolescent alcohol consumption.

AIM: To investigate possible interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter, family relations and maltreatment/sexual abuse on adolescent alcohol-related problem behaviour among male adolescents. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study of a randomized sample of 66 male individuals from a total population of 16- and 19-year adolescents from a Swedish county. Boys, who volunteered to participate answering an alcohol-related problem/behaviour questionnaire, were investigated with regard to interactions between such problems, family function, maltreatment and MAO-A genotype. MEASUREMENTS: MAO-A genotype, family relations history, history of being maltreated or abused and alcohol-related problem behaviour. FINDINGS: Boys with the short (three-repeat) variant of the MAO-A gene, who had been maltreated/abused or came from families with poor relations, showed significantly higher scores of alcohol-related problems. We also found that maltreatment/abuse independently showed the strongest relation to alcohol-related problems among boys in our model. CONCLUSIONS: The results suggest that both maltreatment and MAO-A genotype may be useful for the understanding of male adolescent alcohol-related problem behaviour.

Acute psychotic symptoms in HIV-1 infected patients are associated with increased levels of kynurenic acid in cerebrospinal fluid.

Human immunodeficiency virus type 1 (HIV-1) infection is associated with psychiatric complications including cognitive impairment, affective disorders, and psychosis. Previous studies have revealed a disturbed kynurenine metabolism in these patients leading to increased levels of neuroactive compounds acting at glutamatergic neurotransmission. Kynurenic acid (KYNA), one of these metabolites is a glutamate-receptor antagonist, preferentially blocking the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Increased levels of brain KYNA have been suggested to induce a NMDA receptor hypofunction that is associated with psychotic symptoms. In the present study, we analyze the concentration of KYNA in the cerebrospinal fluid (CSF) from HIV-1 infected patients (n=22), including HIV-1 infected patients with psychotic symptoms (n=8) and HIV-1 infected patients without psychiatric symptoms (n=14). We found that HIV-1 infected patients had significantly higher median concentration of CSF KYNA (3.02nM) compared to healthy controls (1.17nM). Furthermore, CSF KYNA levels were significantly elevated in HIV-1 infected patients with psychotic symptoms (4.54nM) compared to patients with HIV-1 without psychiatric symptoms (2.28nM). Present results indicate that increased levels of CSF KYNA may be associated with development of psychotic symptoms in HIV-1 infected patients.

Adolescent girls and criminal activity: role of MAOA-LPR genotype and psychosocial factors.

Recent findings among boys show that interactions between a polymorphism in the monoamine oxidase A gene promoter region (MAOA-LPR) and psychosocial factors predict criminal activity. The objective of this study was to investigate whether this finding could be extended to adolescent girls. One hundred nineteen female adolescents were recruited among respondents to a cross-sectional study of the total population of 16- and 19-year old girls. These girls constituted a randomly selected sub-sample from groups representing different degrees of risk behavior. The subjects filled in a questionnaire and were interviewed and genotyped with regard to MAOA-LPR. The results indicate that the long, (4-repeat) allele confer an increased risk for criminal behavior in the presence of psychosocial risk. Among girls without social risk, MAOA-LPR genotype was of no importance for criminal behavior. The present results suggest that previous observations on adolescent males, which demonstrate that the short MAOA-LPR genotype and psychosocial adversity interact to predict criminal activity, may not be applicable to females.