Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data.

BACKGROUND: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). METHODS: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. RESULTS: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. CONCLUSIONS: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives.

Dear Doctor Letters regarding citalopram and escitalopram: guidelines vs real-world data.

Dear Doctor Letters (DDLs, Direct Healthcare Professional Communications) from 2011 provided guidance regarding QTc-prolonging effects with risk of torsade de pointes during treatment with citalopram and escitalopram. This study examines the DDLs' effects on prescription behavior. Data from 8842 inpatients treated with citalopram or escitalopram with a primary diagnosis of major depressive disorder (MDD) were derived from a European pharmacovigilance study (Arzneimittelsicherheit in der Psychiatrie, AMSP) from 2001 to 2017. It was examined to what extent new maximum doses were adhered to and newly contraindicated combinations with QTc-prolonging drugs were avoided. In addition, the prescriptions of psychotropic drugs before and after DDLs were compared in all 43,480 inpatients with MDD in the data set. The proportion of patients dosed above the new limit decreased from 8 to 1% in patients ≤ 65 years and from 46 to 23% in patients > 65 years old for citalopram versus 14-5% and 47-31% for escitalopram. Combinations of es-/citalopram with other QTc-prolonging psychotropic drugs reduced only insignificantly (from 35.9 to 30.9%). However, the proportion of patients with doses of quetiapine > 150 mg/day substantially decreased within the combinations of quetiapine and es-/citalopram (from 53 to 35%). After the DDLs, prescription of citalopram decreased and of sertraline increased. The DDLs' recommendations were not entirely adhered to, particularly in the elderly and concerning combination treatments. This might partly be due to therapeutic requirements of the included population. Official warnings should consider clinical needs.

Treatment of depression: Are psychotropic drugs appropriately dosed in women and in the elderly? Dosages of psychotropic drugs by sex and age in routine clinical practice.

BACKGROUND: Several researchers have shown higher concentration-dose ratios of psychotropic drugs in women and the elderly. Therefore, lower dosages of psychotropic drugs may be recommended in women and the elderly. This study describes sex- and age-related dosage of psychotropic drugs prescribed to patients with major depressive disorder (MDD) in routine clinical practice. METHOD: Influence of sex and age on dosages are analysed for the 10 most commonly prescribed drugs in our dataset consisting of 32,082 inpatients with MDD. Data stems from the European drug safety program "Arzneimittelsicherheit in der Psychiatrie". The observed sex and age differences in prescriptions are compared to differences described in literature on age- and gender-related pharmacokinetics. RESULTS: Among patients over 65 years, a statistically significant decrease in dosages with increasing age (between 0.65% and 2.83% for each increasing year of age) was observed, except for zopiclone. However, only slight or no influence of sex-related adjustment of dosage in prescriptions was found. CONCLUSION: Age appears to influence adjustment of dosage in most psychotropic drugs, but to a lower extent than data on age-related pharmacokinetics suggests. Although literature also suggests that lower dosages of psychotropic drugs may be appropriate for females, this study found women are usually prescribed the same dosage as men.

Monitoring the effects of therapeutic interventions in depression through self-assessments.

The treatment of major psychiatric disorders is an arduous and thorny path for the patients concerned, characterized by polypharmacy, massive adverse side effects, modest prospects of success, and constantly declining response rates. The more important is the early detection of psychiatric disorders prior to the development of clinically relevant symptoms, so that people can benefit from early interventions. A well-proven approach to monitoring mental health relies on voice analysis. This method has been successfully used with psychiatric patients to 'objectively' document the progress of improvement or the onset of relapse. The studies with psychiatric patients over 2-4 weeks demonstrated that daily voice assessments have a notable therapeutic effect in themselves. Therefore, daily voice assessments appear to be a lowthreshold form of therapeutic means that may be realized through self-assessments. To evaluate performance and reliability of this approach, we have carried out a longitudinal study on 82 university students in 3 different countries with daily assessments over 2 weeks. The sample included 41 males (mean age 24.2±3.83 years) and 41 females (mean age 21.6±2.05 years). Unlike other research in the field, this study was not concerned with the classification of individuals in terms of diagnostic categories. The focus lay on the monitoring aspect and the extent to which the effects of therapeutic interventions or of behavioural changes are visible in the results of self-assessment voice analyses. The test persons showed an over-proportionally good adherence to the daily voice analysis scheme. The accumulated data were of generally high quality: sufficiently high signal levels, a very limited number of movement artifacts, and little to no interfering background noise. The method was sufficiently sensitive to detect: i) habituation effects when test persons became used to the daily procedure; and ii) short-term fluctuations that exceeded prespecified thresholds and reached significance. Results are directly interpretable and provide information about what is going well, what is going less well, and where there is a need for action. The proposed self-assessment approach was found to be well-suited to serve as a health-monitoring tool for subjects with an elevated vulnerability to psychiatric disorders or to stress-induced mental health problems. Daily voice assessments are in fact a low-threshold form of therapeutic means that can be realized through selfassessments, that requires only little effort, can be carried out in the test person's own home, and has the potential to strengthen resilience and to induce positive behavioural changes.

Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

Early Detection of the Risk of Developing Psychiatric Disorders: A Study of 461 Chinese University Students under Chronic Stress.

Chronic stress, a characteristic of modern time, has a significant impact on general health. In the context of psychiatric disorders, insufficient coping behavior under chronic stress has been linked to higher rates of (1) depressive symptoms among subjects of the general population, (2) relapse among patients under treatment for clinical depression, and (3) negative symptoms among subjects with an elevated vulnerability to psychosis. In this normative study we assessed basic coping behavior among 461 Chinese freshman university students along with their consumption behavior and general health in terms of regular exercises, physical health, psychosomatic disturbances, and mental health. The assessments relied on two instruments that have already demonstrated their capability of (1) reliably detecting insufficient coping behavior under chronic stress and (2) reliably quantifying the interrelation between coping behavior and mental health in the Western world. Thus, we aimed to complement existing data and to develop a generally available, socioculturally independent tool that can be used for the early detection of subjects with an elevated risk of mental health problems. Structural analyses yielded essentially the same scales "activity" and "defeatism" as previous studies on 2,500 students from Switzerland, Italy, Spain, the USA, and Argentina. These scales explained 74.3% of the observed variance in coping behavior among the 461 Chinese students. We found highly significant correlations (p < 0.0001) between the "defeatism" scale on the one hand, and the scales "regular use of medicine," "psychosomatic disturbances," and "impaired mental health" on the other. Particularly intriguing was the finding that a neural net classifier could be constructed to identify students with the highest contributions to the interrelation between "coping behavior" and "mental health," yielding a correlation coefficient as high as r = 0.597 for the respective subgroup. Based on the normative data, an online tool for risk assessments was developed with immediate feedback to users. This study provided another piece of evidence regarding the close link between basic coping behavior and mental health, across cultures and ethnicities. In consequence, our approach to quantifying basic coping behavior, along with other risk factors, can be expected to clear the way for an "early" detection of students with an elevated risk of stress-related mental health problems, nota bene prior to the development of clinically relevant symptoms. The socioeconomic impact of the potential prevention of depressive -disorders, and psychiatric disorders in general, may be enormous.

Cutaneous adverse drug reactions to psychotropic drugs and their risk factors - a case-control study.

Cutaneous adverse drug reactions (CADRs) in patients with psychotropic drugs are common. Large studies on the relevant drugs and other risk factors are still scarce. 594 cases of severe CADRs ("cases") were compared with 8085 cases of other adverse drug reactions ("non-cases") documented in a pharmacovigilance program in psychiatry (AMSP) from 1993 to 2014. Logistic regression was carried out to determine risk factors and between-drug differences. CADRs were relatively more prevalent in patients treated with clomipramine, maprotiline, carbamazepine, lamotrigine, acamprosate, clomethiazole and disulfiram as well as with antidepressants and anticonvulsants as drug classes (p < 0.01). For these drugs, significantly more women were found in patients using maprotiline, lamotrigine (not carbamazepine) and in the groups of antidepressants, tricyclics and anticonvulsants (p < 0.01). Women were more vulnerable to CADRs (67% in cases and 56% in non-cases, p < 0.01). The significantly higher rate of CADRs in women was mainly observed under age of 50 years, i.e. during female reproductive years. In a multivariate logistic regression, female sex, the diagnostic group ICD F1 (substance abuse), maprotiline, carbamazepine, lamotrigine and clomethiazole were identified as risk factors of CADRs. The case/non-case approach allowed to identify risk factors based on empirical data rather than experts' evaluations. The new findings of substance abuse and clomethiazole as risk factors for CADRs have to be confirmed in further studies. Since CADRs can be life-threatening, it is important to be aware of risk factors, especially women during their reproductive period and with lamotrigine treatment.

Inflammatory processes and schizophrenia: two independent lines of evidence from a study of twins discordant and concordant for schizophrenic disorders.

The concept of twin concordance involves quantifying the resemblance between co-twins in an "objective" and reproducible way. Yet, quantifying resemblance in the case of complex psychiatric traits like schizophrenic disorders leads to methodological problems, as the yes-no dichotomy of diagnostic schemata does not allow one to assess between-subject differences in psychopathology patterns sufficiently accurately. Therefore, we relied on a multidimensional, quantitative concordance measure that provided a high resolution and differentiation when assessing the resemblance of psychopathology patterns. This concordance measure was central to our investigations into the potential link between schizophrenic disorders and aberrancies of the inflammatory response system. Specifically, we aimed to determine the extent to which (1) the observed variation of between-subject psychopathology concordance among 100 schizophrenic patients and (2) the observed variation of within-pair psychopathology concordance among 71 twin pairs can be explained by immunoglobulin M (IgM) levels. To accomplish this goal, we had to "gauge" in a first step the concordance measure's performance by (1) comparing the psychopathology patterns of 269 index cases suffering from functional psychoses with the respective patterns of the 350 "affecteds" among their first-degree relatives; (2) systematically comparing the psychopathology patterns of 100 unrelated patients with a diagnosis of schizophrenic disorders with each other; and (3) detailing the within-pair concordance of elementary traits among 2734 healthy twin pairs. As to the role of active immune processes in the context of schizophrenic disorders, we found that there exists a 20-30% subgroup of patients for whom aberrancies of the inflammatory response system, as quantified through IgM levels, appeared to be linked to the pathogenesis of schizophrenic disorders (r = 0.7515/0.8184, p < 0.0001). The variation of within-pair psychopathology concordance among twins with schizophrenic disorders was found to be "explainable" in part by chronically elevated IgM levels (24.5% of observed phenotypic variance; p = 0.0434), thus suggesting that monozygotic twins concordant for schizophrenic disorders may possess a less "robust" variant of the inflammatory response system which can more easily be triggered by exogenous factors than the more "robust" variants of discordant pairs. Though the underlying biological mechanisms remain to be detected, our data have cleared the way for an early identification of patients with schizophrenic disorders for whom the inflammatory response system may be a target for therapeutic intervention. Moreover, our results will likely lead to new treatment strategies that involve elements of personalized medicine.

Image analysis of neutrophil nuclear morphology: Learning about phenotypic range and its reliable analysis from patients with pelger-Huët-anomaly and treated with colchicine.

The nuclear morphology of neutrophils depends on different endogenous and exogenous factors, which can lead to hypo- or hypersegmentation of the normally 2-4 segmented nucleus. Hyposegmentation can be due to mutations in the LBR-gene (Pelger-Huët-Anomaly) or can be induced, for example, by colchicine treatment. The range of this phenotypic variation is known as "norm of reaction," which can be of major relevance for clinical diagnosis and therapeutic intervention. In this project, we studied the norm of reaction in 26 subjects with 0-3 wild type LBR alleles. In addition, the phenotypic variation was analyzed in 3 patients with Familial Mediterranean Fever (FMF), before and after colchicine treatment. We measured the phenotype nuclear segmentation of neutrophils based on two conventional qualitative methods, the "rule of threads" and the "rule of thirds." In addition, we tested a morphometric quantitative approach, the "circularity index." The circularity index was superior in cases with hyposegmentation; the rule of thirds with respect to hypersegmentation. Approximately 65% of the observed phenotypic variance was explainable by the number of LBR wild type alleles. The gene-dosage effect followed a non-additive, hysteresis-like characteristic with lower and upper plateaus. Colchicine treatment had a clear, although minor phenotypic effect compared to the number of LBR wild type genes or the mutation type. Thus, the nuclear morphology of granulocytes and its norm of reaction can be regarded as an excellent model both for detailing the interplay between endogenous and exogenous factors and for clinical diagnostic purposes. © 2016 International Clinical Cytometry Society.

Assessing Chronic Stress, Coping Skills, and Mood Disorders through Speech Analysis: A Self-Assessment 'Voice App' for Laptops, Tablets, and Smartphones.

BACKGROUND: Computerized speech analysis (CSA) is a powerful method that allows one to assess stress-induced mood disturbances and affective disorders through repeated measurements of speaking behavior and voice sound characteristics. Over the past decades CSA has been successfully used in the clinical context to monitor the transition from 'affectively disturbed' to 'normal' among psychiatric patients under treatment. This project, by contrast, aimed to extend the CSA method in such a way that the transition from 'normal' to 'affected' can be detected among subjects of the general population through 10-20 self-assessments. METHODS: Central to the project was a normative speech study of 5 major languages (English, French, German, Italian, and Spanish). Each language comprised 120 subjects stratified according to gender, age, and education with repeated assessments at 14-day intervals (total n = 697). In a first step, we developed a multivariate model to assess affective state and stress-induced bodily reactions through speaking behavior and voice sound characteristics. Secondly, we determined language-, gender-, and age-specific thresholds that draw a line between 'natural fluctuations' and 'significant changes'. Thirdly, we implemented the model along with the underlying methods and normative data in a self-assessment 'voice app' for laptops, tablets, and smartphones. Finally, a longitudinal self-assessment study of 36 subjects was carried out over 14 days to test the performance of the CSA method in home environments. RESULTS: The data showed that speaking behavior and voice sound characteristics can be quantified in a reproducible and language-independent way. Gender and age explained 15-35% of the observed variance, whereas the educational level had a relatively small effect in the range of 1-3%. The self-assessment 'voice app' was realized in modular form so that additional languages can simply be 'plugged in' once the respective normative data become available. Results of the longitudinal self-assessment study in home environments demonstrated that CSA methods work well under most circumstances. CONCLUSIONS: We have successfully developed and tested a self-assessment CSA method that can monitor transitions from 'normal' to 'affected' in subjects of the general population in the broader context of mood disorders. Our easy-to-use 'voice app' evaluates sequences of 10-20 repeated assessments and watches for affect- and stress-induced deviations from baseline that exceed language-, gender-, and age-specific thresholds. Specifically, the 'voice app' provides users with stress-related 'biofeedback' and can help to identify that 10-15% subgroup of the general population that exhibits insufficient coping skills under chronic stress and may benefit from early detection and intervention prior to developing clinically relevant symptoms.

Quantifying insufficient coping behavior under chronic stress: a cross-cultural study of 1,303 students from Italy, Spain and Argentina.

The question of how to quantify insufficient coping behavior under chronic stress is of major clinical relevance. In fact, chronic stress increasingly dominates modern work conditions and can affect nearly every system of the human body, as suggested by physical, cognitive, affective and behavioral symptoms. Since freshmen students experience constantly high levels of stress due to tight schedules and frequent examinations, we carried out a 3-center study of 1,303 students from Italy, Spain and Argentina in order to develop socioculturally independent means for quantifying coping behavior. The data analysis relied on 2 self-report questionnaires: the Coping Strategies Inventory (COPE) for the assessment of coping behavior and the Zurich Health Questionnaire which assesses consumption behavior and general health dimensions. A neural network approach was used to determine the structural properties inherent in the COPE instrument. Our analyses revealed 2 highly stable, socioculturally independent scales that reflected basic coping behavior in terms of the personality traits activity-passivity and defeatism-resilience. This replicated previous results based on Swiss and US-American data. The percentage of students exhibiting insufficient coping behavior was very similar across the study sites (11.5-18.0%). Given their stability and validity, the newly developed scales enable the quantification of basic coping behavior in a cost-efficient and reliable way, thus clearing the way for the early detection of subjects with insufficient coping skills under chronic stress who may be at risk of physical or mental health problems.

Affective state and voice: cross-cultural assessment of speaking behavior and voice sound characteristics--a normative multicenter study of 577 + 36 healthy subjects.

BACKGROUND: Human speech is greatly influenced by the speakers' affective state, such as sadness, happiness, grief, guilt, fear, anger, aggression, faintheartedness, shame, sexual arousal, love, amongst others. Attentive listeners discover a lot about the affective state of their dialog partners with no great effort, and without having to talk about it explicitly during a conversation or on the phone. On the other hand, speech dysfunctions, such as slow, delayed or monotonous speech, are prominent features of affective disorders. METHODS: This project was comprised of four studies with healthy volunteers from Bristol (English: n = 117), Lausanne (French: n = 128), Zurich (German: n = 208), and Valencia (Spanish: n = 124). All samples were stratified according to gender, age, and education. The specific study design with different types of spoken text along with repeated assessments at 14-day intervals allowed us to estimate the 'natural' variation of speech parameters over time, and to analyze the sensitivity of speech parameters with respect to form and content of spoken text. Additionally, our project included a longitudinal self-assessment study with university students from Zurich (n = 18) and unemployed adults from Valencia (n = 18) in order to test the feasibility of the speech analysis method in home environments. RESULTS: The normative data showed that speaking behavior and voice sound characteristics can be quantified in a reproducible and language-independent way. The high resolution of the method was verified by a computerized assignment of speech parameter patterns to languages at a success rate of 90%, while the correct assignment to texts was 70%. In the longitudinal self-assessment study we calculated individual 'baselines' for each test person along with deviations thereof. The significance of such deviations was assessed through the normative reference data. CONCLUSIONS: Our data provided gender-, age-, and language-specific thresholds that allow one to reliably distinguish between 'natural fluctuations' and 'significant changes'. The longitudinal self-assessment study with repeated assessments at 1-day intervals over 14 days demonstrated the feasibility and efficiency of the speech analysis method in home environments, thus clearing the way to a broader range of applications in psychiatry.

Insufficient coping behavior under chronic stress and vulnerability to psychiatric disorders.

BACKGROUND: Epidemiological data indicate that 75% of subjects with major psychiatric disorders have their onset of illness in the age range of 17-24 years. An estimated 35-50% of college and university students drop out prematurely due to insufficient coping skills under chronic stress, while 85% of students receiving a psychiatric diagnosis withdraw from college/university prior to the completion of their education. In this study, we aimed at developing standardized means of identifying students with insufficient coping skills under chronic stress and at risk for mental health problems. SAMPLING AND METHODS: A sample of 1,217 college students from 3 different sites in the USA and Switzerland completed 2 self-report questionnaires: the Coping Strategies Inventory (COPE) and the Zurich Health Questionnaire (ZHQ), which assesses 'regular exercises', 'consumption behavior', 'impaired physical health', 'psychosomatic disturbances' and 'impaired mental health'. The data were subjected to structure analyses by means of a neural network approach. We found 2 highly stable and reproducible COPE scales that explained the observed interindividual variation in coping behavior sufficiently well and in a socioculturally independent way. The scales reflected basic coping behavior in terms of 'activity-passivity' and 'defeatism-resilience', and in the sense of stable, socioculturally independent personality traits. RESULTS: Correlation analyses carried out for external validation revealed a close relationship between high scores on the defeatism scale and impaired physical and mental health. This underlined the role of insufficient coping behavior as a risk factor for physical and mental health problems. CONCLUSION: The combined COPE and ZHQ instruments appear to constitute powerful screening tools for insufficient coping skills under chronic stress and for risks of mental health problems.

In need of psychiatric help--leave a message after the beep.

BACKGROUND/AIM: Every day, a substantial proportion of the general population experiences the distressing and frightening signs of an upcoming psychiatric illness. The consequences can be enormous because severe psychiatric disorders typically cause the loss of the ability to work and often mean a long-term burden for both the patients and their families. Even though most developed countries have an exceptionally high density of general practitioners and psychiatrists in private practice, getting a mental health appointment and seeing a doctor is often very difficult for patients with acute psychiatric symptoms. This study aimed at quantifying the time delay involved in seeking medical attendance when psychiatric disorders begin to develop. METHODS: Two female actors with well-proven experiences of realistically simulating the clinical presentation of depression and psychotic disorders made systematic phone calls to 106 psychiatrists in private practice and 106 general practitioners (GPs) of the Zurich City area. The actors asked for an appointment at the doctor's earliest convenience due to acute psychiatric symptoms. We assessed (1) the number of phone calls it took to reach each doctor; (2) the time it took to book an appointment; (3) the time span between the first phone call and the earliest available appointment, and (4) the possibility of personal contact with a doctor prior to booking the appointment. RESULTS: A total of 383 phone calls were made by the two actors (227 to psychiatrists and 156 to GPs) which resulted in analyzable data from 102 psychiatrist and 106 GP practices. Two thirds (68%) of the phone calls to the psychiatrists in private practice were answered by voice mail, compared to 21% among the GPs. A personal contact was established with 56% of the psychiatrists and 95% of the GPs. On average, 7.3 phone calls were necessary to successfully book an appointment with a psychiatrist. Almost half of the psychiatrists (45.6%) were not accepting new patients so appointments were able to be booked in less than one third of cases (30.4%). The situation was significantly better with GPs (p < 0.002) but depended on clinical diagnosis (p < 0.01). The waiting time to seeing a psychiatrist often far exceeded 7 days. CONCLUSIONS: A high density of psychiatrists in private practice does not necessarily improve the long and troublesome circumstances of obtaining a mental health appointment in acute psychiatric situations. Under these circumstances, a considerable proportion of patients might give up prior to seeing a doctor. This has important implications--many patients could miss the potential benefits from timely therapeutic interventions which can significantly modify both the acute and long-term course of the illness. The situation might be improved if psychiatrists and GPs joined forces in the form of group practices or networks as this would readily ensure (1) a rapid mental health triage by assessing and categorizing the urgency of mental health-related problems, and (2) timely therapeutic interventions whenever indicated.

AKAP13, CACNA1, GRIK4 and GRIA1 genetic variations may be associated with haloperidol efficacy during acute treatment.

We previously investigated a sample of psychotic patients acutely ill and acutely treated with haloperidol in the search for genetic predictors of response at PANSS scores during the first month of treatment. In the present work we extend the analysis to a wider panel of genetic variations including SNPs harbored by genes whose products are involved in molecular pathways consistent with the latest results of genome-wide association studies (GWAS) of antipsychotic efficacy. 96 Patients were investigated. The results were replicated in an independent sample of bipolar manic patients treated with antipsychotics (n tot=470, the sample was retrieved from the STEP-BD). Outcomes were the PANSS variation through time in the first sample, and changes of mania symptomatology at any two consecutive observations in the public available STEP-BD replication sample. A list of variations harbored by AKAP13, CACNA1, GRIK4 and GRIA1 were found to be significantly associated with outcome in both samples (different set of variations for each sample). Results did not survived multiple testing in the original sample but were replicated in both samples. This finding stresses the relevance of the glutamatergic system and regulatory molecular cascades in antipsychotic response. Nonetheless, the level of significance and the indirect and incomplete replication mandate cautiousness and further replication.

Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol.

The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation.

No association of a set of candidate genes on haloperidol side effects.

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (~ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects.

Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol.

BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments. OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol. METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia. CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression.

OBJECTIVE: To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. METHODS: Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. RESULTS: 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). CONCLUSION: Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

Lack of association between 71 variations located in candidate genes and response to acute haloperidol treatment.

RATIONALE: The antipsychotic pharmacological treatment effectiveness and side effects are at least partially driven by the genetic personal background. OBJECTIVES: In the present study, 71 genetic variations located in 21 candidate genes were investigated as modulators of the haloperidol efficacy and side effects in a sample of 101 acutely ill psychotic patients. METHODS: Patients were assessed at days 0, 7, 14, 21, and 28 (Positive and Negative Syndrome Scale (PANSS) test) and days 1, 3, 7, 14, 21, and 28 (UKU, BAS, and ESRS tests). Haloperidol plasma levels were measured at the same timepoints. RESULTS: None of the 71 variations were associated with response to treatment or with incidence of side effects passed a multiple testing threshold. A marginal association was detected between two haplotypes within the signal transducer and activator of transcription 4 gene and PANSS positive and dopamine beta-hydroxylase with PANSS negative scores (p = 0.004 and p = 0.008, respectively). CONCLUSIONS: In conclusion, no major association was observed between the investigated variations and the efficacy profile of haloperidol.