Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia

Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today's acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: "F2x.x"; n = 94; "F2 patients") or depressive disorders (ICD-10: "F3x.x"; n = 226; "F3 patients"). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history» and «severity at baseline» played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2-3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the "natural" time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here

Systematic review of interventions for treating or preventing antipsychotic-induced tardive dyskinesia

Background: Antipsychotic medication can cause tardive dyskinesia (TD) – late-onset, involuntary, repetitive movements, often involving the face and tongue. TD occurs in > 20% of adults taking antipsychotic medication (first-generation antipsychotics for > 3 months), with this proportion increasing by 5% per year among those who continue to use these drugs. The incidence of TD among those taking newer antipsychotics is not different from the rate in people who have used older-generation drugs in moderate doses. Studies of TD have previously been found to be limited, with no treatment approach shown to be effective. Objectives: To summarise the clinical effectiveness and safety of treatments for TD by updating past Cochrane reviews with new evidence and improved methods; to undertake public consultation to gauge the importance of the topic for people living with TD/the risk of TD; and to make available all data from relevant trials. Data sources: All relevant randomised controlled trials (RCTs) and observational studies. Review methods: Cochrane review methods, network meta-analysis (NMA). Design: Systematic reviews, patient and public involvement consultation and NMA. Setting: Any setting, inpatient or outpatient. Participants: For systematic reviews, adults with TD who have been taking a stable antipsychotic drug dose for > 3 months. Interventions: Any, with emphasis on those relevant to UK NHS practice. Main outcome measures: Any measure of TD, global assessments and adverse effects/events. Results: We included 112 studies (nine Cochrane reviews). Overall, risk of bias showed little sign of improvement over two decades. Taking the outcome of ‘TD symptoms improved to a clinically important extent’, we identified two trials investigating reduction of antipsychotic dose [n = 17, risk ratio (RR) 0.42, 95% confidence interval (CI) 0.17 to 1.04; very low quality]. Switching was investigated twice in trials that could not be combined (switching to risperidone vs. antipsychotic withdrawal: one RCT, n = 42, RR 0.45, 95% CI 0.23 to 0.89; low quality; switching to quetiapine vs. haloperidol: one RCT, n = 45, RR 0.80, 95% CI 0.52 to 1.22; low quality). In addition to RCTs, six observational studies compared antipsychotic discontinuation with decreased or increased dosage, and there was no clear evidence that any of these strategies had a beneficial effect on TD symptoms (very low-quality evidence). We evaluated the addition to standard antipsychotic care of several treatments, but not anticholinergic treatments, for which we identified no trials. We found no clear effect of the addition of either benzodiazepines (two RCTs, n = 32, RR 1.12, 95% CI 0.6 to 2.09; very low quality) or vitamin E (six RCTs, n = 264, RR 0.95, 95% CI 0.89 to 1.01; low quality). Buspirone as an adjunctive treatment did have some effect in one small study (n = 42, RR 0.53, 95% CI 0.33 to 0.84; low quality), as did hypnosis and relaxation (one RCT, n = 15, RR 0.45, 95% CI 0.21 to 0.94; very low quality). We identified no studies focusing on TD in people with dementia. The NMA model found indirect estimates to be imprecise and failed to produce useful summaries on relative effects of interventions or interpretable results for decision-making. Consultation with people with/at risk of TD highlighted that management of TD remains a concern, and found that people are deeply disappointed at the length of time it has taken researchers to address the issue. Limitations: Most studies remain small and poorly reported. Conclusions: Clinicians, policy-makers and people with/at risk of TD are little better informed than they were decades ago. Underpowered trials of limited quality repeatedly fail to provide answers. Future work: TD reviews have data from current trials extracted, tabulated and traceable to source. The NMA highlights one context in which support for this technique is ill advised. All relevant trials, even if not primarily addressing the issue of TD, should report appropriate binary outcomes on groups of people with this problem. Randomised trials of treatments for people with established TD are indicated. These should be large (> 800 participants), necessitating accrual through accurate local/national registers, including an intervention with acceptable treatments and recording outcomes used in clinical practice. Study registration: This study is registered as PROSPERO CRD4201502045. Funding: The National Institute for Health Research Health Technology Assessment programme

Atypical antipsychotics in the treatment of schizophrenia

Over the last few years atypical antipsychotics have been used increasingly in the pharmacological treatment of schizophrenia. This review provides an overview of the pharmacological and clinical characteristics of atypical antipsychotics. In particular we discuss their efficacy in treating psychotic and negative symptoms as well as treatment-refractory patients. The most important side effects as well as their possible interactions are reviewed in detail. Recommendations for the clinical use are given

Polypharmacy in psychiatry and weight gain: longitudinal study of 832 patients hospitalized for depression or schizophrenia, along with data of 3180 students from Europe, the U.S., South America, and China.

Epidemiologic data indicate that overweight and obesity are on the rise worldwide. Psychiatric patients are particularly vulnerable in this respect as they have an increased prevalence of overweight and obesity, and often experience rapid, highly undesirable weight gain under psychotropic drug treatment. Current treatment strategies in psychiatry are oriented towards polypharmacy, so that the information on drug-induced weight gain from earlier monotherapy studies is of very limited validity. We have analyzed the longitudinal data of 832 inpatients with ICD-10 diagnoses of either F2 (schizophrenia; n = 282) or F3 (major depression; n = 550) with the goal of ranking treatment regimens in terms of weight gain, side effects, and response to treatment. The patient data were complemented by the data of 3180 students aged 18-22 years, with which we aimed to identify factors that enable the early detection and prevention of obesity and mental health problems. After 3 weeks of treatment, 47.7% of F2 patients and 54.9% of F3 patients showed a weight gain of 2 kg and more. Major predictive factors were "starting weight" (r = 0.115), "concurrent medications" (r = 0.176), and "increased appetite"(r = 0.275). Between 11 and 30% of the observed variance in weight gain could be explained by these factors, complemented by sex and age. The comparison between monotherapy (n = 409) and polypharmacy (n = 399) revealed significant drawbacks for polypharmacy: higher weight gain (p = 0.0005), more severe side effects (p = 0.0011), and lower response rates (F2: p = 0.0008); F3: p = 0.0101). The data of 3180 students made it clear that overweight and obesity often begin early in life among those affected, and are interconnected with personality traits, while increasing the risk of developing psychosomatic disturbances, mental health problems, or somatic illnesses. Although the available data did not readily lead to a comprehensive, clinically applicable model of unwanted weight gain, our results have nevertheless demonstrated that there are ways to successfully counteract such weight gain at early stages of treatment

Inflammatory processes linked to major depression and schizophrenic disorders and the effects of polypharmacy in psychiatry: evidence from a longitudinal study of 279 patients under therapy

Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors “diagnosis”, “previous history”, “severity at baseline”, “age”, “gender”, and “psychiatrist in charge”; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: “F3x.x”; n = 195) or schizophrenic disorders (ICD-10: “F2x.x”; n = 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data (“supervised learning”). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (p < 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of r = 0.746 (p = 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of r = 0.644 (p = 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today’s acute treatment of psychiatric disorders. Given the large proportion of patients with unwanted side effects and the strong correlation between side effects and the number of drugs, polypharmacy approaches are not equally suited for every patient. In terms of efficacy, there are no advantages of polypharmacy over monotherapy. Most notably, our study appears to have cleared the way for the reliable identification of a subgroup of patients for whom the inflammatory response system is a promising target of therapeutic intervention

Analysis of genetic diversity in patients with major psychiatric disorders versus healthy controls: A molecular-genetic study of 1698 subjects genotyped for 100 candidate genes (549 SNPs).

BACKGROUND This study analyzed the extent to which irregularities in genetic diversity separate psychiatric patients from healthy controls. METHODS Genetic diversity was quantified through multidimensional "gene vectors" assembled from 4 to 8 polymorphic SNPs located within each of 100 candidate genes. The number of different genotypic patterns observed per gene was called the gene's "diversity index". RESULTS The diversity indices were found to be only weakly correlated with their constituent number of SNPs (20.5 % explained variance), thus suggesting that genetic diversity is an intrinsic gene property that has evolved over the course of evolution. Significant deviations from "normal" diversity values were found for (1) major depression; (2) Alzheimer's disease; and (3) schizoaffective disorders. Almost one third of the genes were correlated with each other, with correlations ranging from 0.0303 to 0.7245. The central finding of this study was the discovery of "singular genes" characterized by distinctive genotypic patterns that appeared exclusively in patients but not in healthy controls. Neural Nets yielded nonlinear classifiers that correctly identified up to 90 % of patients. Overlaps between diagnostic subgroups on the genotype level suggested that (1) diagnoses-crossing vulnerabilities are likely involved in the pathogenesis of major psychiatric disorders; (2) clinically defined diagnoses may not constitute etiological entities. CONCLUSION Detailed analyses of the variation of genotypic patterns in genes along with the correlation between genes lead to nonlinear classifiers that enable very robust separation between psychiatric patients and healthy controls on the genotype level

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 &lt; 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

Schizophrenia and smoking: Evidence for a common neurobiological basis?

Several previous investigations have suggested that the gene for the α7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the α7-nicotinic receptor, 2) to test the diagnostic specificity of α7-receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the α7-nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co-occurrence of psychopathology with no clear-cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of α7-receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction

Gemeindenahe psychiatrische Akutbehandlung in Gastfamilien. Kostengünstige Alternative zum Klinikaufenthalt bei hoher Patientenzufriedenheit

BACKGROUND: Over recent decades, institutional psychiatric care has shifted its focus from traditional inpatient treatment to a variety of more advanced outpatient services. Within this context, a new "crisis home" programme (CHP) was launched in Zurich on 1 January 2005. With this programme, mentally ill patients can avoid hospitalization by living with a host family for a certain time period while receiving standard outpatient care. In this study we addressed the question of whether the quite substantial financial advantages of the Zurich CHP over traditional inpatient care are achieved at the expense of a reduced quality of care. SAMPLE AND METHODS: Between 1 January 2005 and 30 June 2007, a total of 33 patients enrolled in the Zurich CHP with an average stay of 19 days at host families. The vast majority of the patients (85%) were moderately to severely ill at study entry. Of these patients data were collected in a standardized way on the basis of five rating instruments. The statistical data analysis included cross-comparisons with corresponding inpatient data. RESULTS: Results showed that (1) the CHP works well in a routine setting and provides cost-efficient interventions for patients in acute crises; (2) the financial advantages of the Zurich host family programme over traditional inpatient care do not lead to a reduced quality in patient care; (3) patients suffering from severe mental illnesses clearly benefit from this programme, thus avoiding hospitalization. CONCLUSIONS: The Zurich CHP is a cost-efficient alternative to traditional inpatient treatment. Specifically, our results suggest that this type of acute crisis intervention should be established as a standard psychiatric care service