Atypical antipsychotics, also known as second-generation antipsychotics, are commonly prescribed as treatment for psychotic disorders in adults, as well as in children and adolescents with behavioral ...problems. However, in many cases, second-generation antipsychotics have unwanted side effects, such as weight gain, potentially further increasing risk for morbidities including obesity, diabetes, and cardiovascular disease. While various mechanisms for this weight gain have been proposed, including effects on metabolic hormone signaling, recent evidence points to the importance of the gut microbiome in this process. The microbial communities residing within the gut are affected by second-generation antipsychotics and can confer weight gain.
This review summarizes recent findings and presents data linking second-generation antipsychotics, gut microbiota alterations and weight gain. The review focuses on children and adolescent populations, which have not previously received much attention, but are of great interest because they may be most vulnerable to gut microbiome changes and may carry long-term metabolic effects into adulthood.
We present correlations between second-generation antipsychotics, gut microbiota alterations and weight gain, and suggest some mechanisms that may link them. A better understanding of the underlying mechanisms may lead to the design of improved treatments for psychotic disorders with fewer harmful side effects.
Clozapine dose for schizophrenia Subramanian, Selvizhi; Völlm, Birgit A; Huband, Nick ...
Cochrane database of systematic reviews,
06/2017, Letnik:
2017, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background
Schizophrenia and related disorders such as schizophreniform and schizoaffective disorder are serious mental illnesses characterised by profound disruptions in thinking and speech, ...emotional processes, behaviour and sense of self. Clozapine is useful in the treatment of schizophrenia and related disorders, particularly when other antipsychotic medications have failed. It improves positive symptoms (such as delusions and hallucinations) and negative symptoms (such as withdrawal and poverty of speech). However, it is unclear what dose of clozapine is most effective with the least side effects.
Objectives
To compare the efficacy and tolerability of clozapine at different doses and to identify the optimal dose of clozapine in the treatment of schizophrenia, schizophreniform and schizoaffective disorders.
Search methods
We searched the Cochrane Schizophrenia Group's Study‐Based Register of Trials (August 2011 and 8 December 2016).
Selection criteria
All relevant randomised controlled trials (RCTs), irrespective of blinding status or language, that compared the effects of clozapine at different doses in people with schizophrenia and related disorders, diagnosed by any criteria.
Data collection and analysis
We independently inspected citations from the searches, identified relevant s, obtained full articles of relevant s, and classified trials as included or excluded. We included trials that met our inclusion criteria and reported useable data. For dichotomous data, we calculated the relative risk (RR) and the 95% confidence interval (CI) on an intention‐to‐treat basis based on a random‐effects model. For continuous data, we calculated mean differences (MD) again based on a random‐effects model. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.
Main results
We identified five studies that could be included. Each compared the effects of clozapine at very low dose (up to 149 mg/day), low dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). Four of the five included studies were based on a small number of participants. We rated all the evidence reported for the main outcomes of interest as low or very low quality. No data were available for the main outcomes of global state, service use or quality of life.
Very low dose compared to low dose
We found no evidence of effect on mental state between low and very low doses of clozapine in terms of average Brief Psychiatric Rating Scale‐Anchored (BPRS‐A) endpoint score (1 RCT, n = 31, MD 3.55, 95% CI −4.50 to 11.60, very low quality evidence). One study found no difference between groups in body mass index (BMI) in the short term (1 RCT, n = 59, MD −0.10, 95% CI −0.95 to 0.75, low‐quality evidence).
Very low dose compared to standard dose
We found no evidence of effect on mental state between very low doses and standard doses of clozapine in terms of average BPRS‐A endpoint score (1 RCT, n = 31, MD 6.67, 95% CI −2.09 to 15.43, very low quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 58, MD 0.10, 95% CI −0.76 to 0.96, low‐quality evidence)
Low dose compared to standard dose
We found no evidence of effect on mental state between low doses and standard doses of clozapine in terms of both clinician‐assessed clinical improvement (2 RCTs, n = 141, RR 0.76, 95% CI 0.36 to 1.61, medium‐quality evidence) and clinically important response as more than 30% change in BPRS score (1 RCT, n = 176, RR 0.93, 95% CI 0.78 to 1.10, medium‐quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 57, MD 0.20, 95% CI −0.84 to 1.24, low‐quality evidence).
We found some evidence of effect for other adverse effect outcomes; however, the data were again limited.
Very low dose compared to low dose
There was limited evidence that serum triglycerides were lower at low‐dose clozapine compared to very low dose in the short term (1 RCT, n = 59, MD 1.00, 95% CI 0.51 to 1.49).
Low dose compared to standard dose
Weight gain was lower at very low dose compared to standard dose (1 RCT, n = 27, MD −2.70, 95% CI −5.38 to −0.02). Glucose level one hour after meal was also lower at very lose dose (1 RCT, n = 58, MD −1.60, 95% CI −2.90 to −0.30). Total cholesterol levels were higher at very low compared to standard dose (1 RCT, n = 58, n = 58, MD 1.00, 95% CI 0.20 to 1.80).
Low dose compared to standard dose
There was evidence of fewer adverse effects, measured as lower TESS scores, in the low‐dose group in the short term (2 RCTs, n = 266, MD −3.99, 95% CI −5.75 to −2.24); and in one study there was evidence that the incidence of lethargy (RR 0.77, 95% CI 0.60 to 0.97), hypersalivation (RR 0.70, 95% CI 0.57 to 0.84), dizziness (RR 0.56, 95% CI 0.39 to 0.81) and tachycardia (RR 0.57, 95% CI 0.45 to 0.71) was less at low dose compared to standard dose.
Authors' conclusions
We found no evidence of effect on mental state between standard, low and very low dose regimes, but we did not identify any trials on high or very high doses of clozapine. BMI measurements were similar between groups in the short term, although weight gain was less at very low dose compared to standard dose in one study. There was limited evidence that the incidence of some adverse effects was greater at standard dose compared to lower dose regimes. We found very little useful data and the evidence available is generally of low or very low quality. More studies are needed to validate our findings and report on outcomes such as relapse, remission, social functioning, service utilisation, cost‐effectiveness, satisfaction with care, and quality of life. There is a particular lack of medium‐ or long‐term outcome data, and on dose regimes above the standard rate.
Objective To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.Design Population based cohort study with linked data from Medicaid, ...Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality.Setting Nursing homes in the United States.Participants 75 445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥65, were eligible for Medicaid, and lived in a nursing home in 2001-5.Main outcome measures Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders.Results Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.Conclusions Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.
Abstract
These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. ...For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A-F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment-resistant schizophrenia.
Acute and long-term objectives must be linked early in the treatment of schizophrenia. Maintenance therapy is pivotal in relapse prevention. Relapses are serious events that alter disease trajectory ...and are most often related to nonadherence. Patients with schizophrenia have a substantial risk of relapse, especially when they are nonadherent to antipsychotics. Because relapses are accompanied by structural brain changes, worsening symptoms, and increased treatment resistance when medication is resumed, clinicians must monitor nonadherence and offer strategies to avoid or improve it. Long-acting injectable (LAI) antipsychotics have the potential to reduce nonadherence, relapse, rehospitalization, and mortality, even among patients with first-episode schizophrenia and with comorbid substance use disorder. Long-acting formulations can be a very powerful strategy in helping to ensure that patients get the benefit of the medication they have been prescribed, as the use of LAIs is more easily monitored than oral medications due to the nature of their administration to patients. However, prescribers tend to believe that patients have negative attitudes about LAIs and avoid prescribing them. Patients should be offered the option of LAI antipsychotic treatment and should understand the logistics and the potential benefits of the regimen. LAIs differ regarding their initiation strategy, duration, and flexibility of injection intervals, in addition to the differences of the antipsychotic that the LAI formulation is based on. Presentation matters for LAI treatments to be accepted by patients and family members. Clinicians can use certain communication tools to improve their dialogue with patients about the benefits of switching from oral agents.
Background
The symptoms and signs of schizophrenia have been linked to high levels of dopamine in specific areas of the brain (limbic system). Antipsychotic drugs block the transmission of dopamine ...in the brain and reduce the acute symptoms of the disorder. An original version of the current review, published in 2012, examined whether antipsychotic drugs are also effective for relapse prevention. This is the updated version of the aforesaid review.
Objectives
To review the effects of maintaining antipsychotic drugs for people with schizophrenia compared to withdrawing these agents.
Search methods
We searched the Cochrane Schizophrenia Group's Study‐Based Register of Trials including the registries of clinical trials (12 November 2008, 10 October 2017, 3 July 2018, 11 September 2019).
Selection criteria
We included all randomised trials comparing maintenance treatment with antipsychotic drugs and placebo for people with schizophrenia or schizophrenia‐like psychoses.
Data collection and analysis
We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CIs) on an intention‐to‐treat basis based on a random‐effects model. For continuous data, we calculated mean differences (MD) or standardised mean differences (SMD), again based on a random‐effects model.
Main results
The review currently includes 75 randomised controlled trials (RCTs) involving 9145 participants comparing antipsychotic medication with placebo. The trials were published from 1959 to 2017 and their size ranged between 14 and 420 participants. In many studies the methods of randomisation, allocation and blinding were poorly reported. However, restricting the analysis to studies at low risk of bias gave similar results. Although this and other potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear. Antipsychotic drugs were more effective than placebo in preventing relapse at seven to 12 months (primary outcome; drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR 0.38, 95% CI 0.32 to 0.45, number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 3; high‐certainty evidence).
Hospitalisation was also reduced, however, the baseline risk was lower (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR 0.43, 95% CI 0.32 to 0.57, NNTB 8, 95% CI 6 to 14; high‐certainty evidence). More participants in the placebo group than in the antipsychotic drug group left the studies early due to any reason (at seven to 12 months: drug 36% versus placebo 62%, 24 RCTs, n = 3951, RR 0.56, 95% CI 0.48 to 0.65, NNTB 4, 95% CI 3 to 5; high‐certainty evidence) and due to inefficacy of treatment (at seven to 12 months: drug 18% versus placebo 46%, 24 RCTs, n = 3951, RR 0.37, 95% CI 0.31 to 0.44, NNTB 3, 95% CI 3 to 4).
Quality of life might be better in drug‐treated participants (7 RCTs, n = 1573 SMD ‐0.32, 95% CI to ‐0.57 to ‐0.07; low‐certainty evidence); probably the same for social functioning (15 RCTs, n = 3588, SMD ‐0.43, 95% CI ‐0.53 to ‐0.34; moderate‐certainty evidence).
Underpowered data revealed no evidence of a difference between groups for the outcome ‘Death due to suicide’ (drug 0.04% versus placebo 0.1%, 19 RCTs, n = 4634, RR 0.60, 95% CI 0.12 to 2.97,low‐certainty evidence) and for the number of participants in employment (at 9 to 15 months, drug 39% versus placebo 34%, 3 RCTs, n = 593, RR 1.08, 95% CI 0.82 to 1.41, low certainty evidence).
Antipsychotic drugs (as a group and irrespective of duration) were associated with more participants experiencing movement disorders (e.g. at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI 1.25 to 1.85, number needed to treat for an additional harmful outcome (NNTH) 20, 95% CI 14 to 50), sedation (drug 8% versus placebo 5%, 18 RCTs, n = 4078, RR 1.52, 95% CI 1.24 to 1.86, NNTH 50, 95% CI not significant), and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR 1.69, 95% CI 1.21 to 2.35, NNTH 25, 95% CI 20 to 50).
Authors' conclusions
For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs prevents relapse to a much greater extent than placebo for approximately up to two years of follow‐up. This effect must be weighed against the adverse effects of antipsychotic drugs. Future studies should better clarify the long‐term morbidity and mortality associated with these drugs.
Abstract
Background and Hypothesis
Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline ...complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications.
Study Design
Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial. The participants were treated with amisulpride for 4 weeks. Levels of complement and coagulation proteins at baseline were measured using both data-dependent and data-independent mass spectrometry approaches. The primary outcome was remission status at 4 weeks and the secondary outcomes included change in psychotic and functional symptoms over the period of treatment. In addition, immunoassays were performed at baseline for complement C1R, as well as for activation markers C4a and sC5b-9.
Study Results
The plasma level of complement variant C4A was significantly associated with remission at 4 weeks. Moreover, higher levels of several complement and coagulation pathway proteins were associated with a reduction in psychotic symptoms and an improvement in functioning. Immunoassays showed an association of baseline levels of C1R and C4a as well as complement activation marker sC5b-9 levels with treatment response.
Conclusion
The results demonstrated that the response to antipsychotic treatment might be related to pre-treatment levels of plasma complement and coagulation pathway proteins. This is consistent with independent evidence associating immune dysfunction with the pathophysiology of psychosis. Moreover, these results inform the development of novel therapeutic approaches that target the complement system for psychosis.
Although mortality related to psychotropic medications has received much attention in recent years, little is known about the relationship between risk of death and cumulative antipsychotic load, and ...even less about the relationship between mortality and cumulative exposure to antidepressants or benzodiazepines. The authors examined these relationships using nationwide databases.
The authors used prospectively collected nationwide databases to identify all individuals 16-65 years of age with a schizophrenia diagnosis (N=21,492) in Sweden. All-cause and cause-specific mortality rates were calculated as a function of cumulative low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines from 2006 through 2010.
Compared with no exposure, both moderate (adjusted hazard ratio=0.59, 95% CI=0.49-0.70) and high (adjusted hazard ratio=0.75, 95% CI=0.63-0.89) antipsychotic exposures were associated with substantially lower overall mortality. Moderate antidepressant exposure was associated with a lower mortality (adjusted hazard ratio=0.85, 95% CI=0.73-0.98), and high exposure, even lower (adjusted hazard ratio=0.71, 95% CI=0.59-0.86). Exposure to benzodiazepines showed a dose-response relationship with mortality (hazard ratios up to 1.74 95% CI=1.50-2.03).
Moderate and high-dose antipsychotic and antidepressant use were associated with 15%-40% lower overall mortality, whereas chronic high-dose use of benzodiazepines was associated with up to a 70% higher risk of death compared with no exposure. Since patients with anxiety and depressive symptoms may have a higher intrinsic risk of death, the finding for benzodiazepines may be attributable to some extent to residual confounding.
Objective:
To provide a concise review of the new Food and Drug Administration (FDA)-approved antipsychotic, lumateperone, for use in schizophrenia.
Data Sources:
A literature search of PubMed was ...performed (January 2000 to May 2020) using the following key terms: lumateperone, Caplyta, and ITI-007. Abstracts from conferences, review articles, clinical trials, and drug monographs were reviewed.
Study Selection and Data Extraction:
Relevant English-language monographs and studies conducted in humans were considered.
Data Synthesis:
Lumateperone was FDA approved for the treatment of schizophrenia in December 2019 based on 2 published randomized, double-blind, placebo-controlled trials. Lumateperone’s pharmacology is consistent with that of other second-generation antipsychotics in that it has a higher affinity for the serotonin (5-HT2A) receptors compared with dopamine (D2) receptors but with lower affinities for α-1 and histaminergic receptors. In addition, it serves as a presynaptic dopamine partial agonist, serotonin reuptake inhibitor, and an indirect modulator of glutamatergic systems. Based on the 4-week clinical trials, lumateperone was well tolerated. Most common treatment-emergent adverse events were headache, somnolence, and dizziness.
Relevance to Patient Care and Clinical Practice:
At this time, lumateperone had a statistically significant reduction in Positive and Negative Syndrome Scale when compared with placebo and was not significantly associated with the extrapyramidal symptoms (EPS) and metabolic adverse effects commonly seen with other antipsychotics.
Conclusions:
Lumateperone has the potential to benefit individuals with schizophrenia who are intolerant to the EPSs or metabolic adverse effects of other antipsychotics. However, further head-to-head trials with commercially available antipsychotics are still required to assist in establishing its role in treatment.
•Antipsychotic efficacy appeared to be dose-dependent in the acute treatment of schizophrenia.•Many antipsychotic-induced adverse effects appeared to be increased in a dose-dependent manner.•A higher ...lifetime cumulative antipsychotic dose may contribute to higher mortality.
Antipsychotics are a cornerstone of pharmacological treatment of schizophrenia. Improved understanding of the dose-response relationship of antipsychotics in terms of efficacy, adverse effects, and mortality can help to optimize the pharmacological treatment of schizophrenia.
This narrative literature review summarizes current evidence on the relationship of antipsychotic dose with efficacy, adverse effects, and mortality in patients with schizophrenia.
The efficacy of antipsychotics generally appeared to be highly dose-dependent in the acute phase of schizophrenia, with each antipsychotic having a specific dose-response curve. The presence or absence of dose-dependency and its extent varied according to the type of adverse effect. Parkinsonism, hyperprolactinemia, weight gain, and neurocognitive impairment appeared to be dose-related. The following adverse effects might be at least somewhat dose-dependent: akathisia, tardive dyskinesia, osteoporosis, sexual dysfunction, diabetes mellitus, myocardial infarction, stroke, thromboembolism, QT interval prolongation, anticholinergic adverse effects, somnolence, pneumonia, hip fracture, and neuroleptic malignant syndrome. In contrast, the relationships of antipsychotic dose with dyslipidemia, hypotension, seizure, sialorrhea, and neutropenia and agranulocytosis remained unclear due to mixed findings and/or limited data. Although a higher lifetime cumulative antipsychotic dose might contribute to higher mortality, it is still difficult to conclude whether mortality increases in a dose-dependent manner.
These findings could help clinicians to optimize antipsychotic treatment in patients with schizophrenia by balancing risks and benefits in clinical practice. However, further investigations with larger sample sizes and more robust study designs that focus on each antipsychotic agent are needed.
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