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Are adult stressful life events associated with psychotic relapse? A systematic review of 23 studies.
Martland, N, Martland, R, Cullen, AE, Bhattacharyya, S
Psychological medicine. 2020;(14):2302-2316
Abstract
Relapse rates among individuals with psychotic disorders are high. In addition to the financial burden placed on clinical services, relapse is associated with worse long-term prognosis and poorer quality of life. Robust evidence indicates that stressful life events commonly precede the onset of the first psychotic episode; however, the extent to which they are associated with relapse remains unclear. The aim of this systematic review is to summarize available research investigating the association between recent stressful life events and psychotic relapse or relapse of bipolar disorder if the diagnosis included psychotic symptoms. PsycINFO, Medline and EMBASE were searched for cross-sectional, retrospective and prospective studies published between 01/01/1970 and 08/01/2020 that investigated the association between adult stressful life events and relapse of psychosis. Study quality was assessed using the Effective Public Health Practice Project guidelines. Twenty-three studies met eligibility criteria (prospective studies: 14; retrospective studies: 6; cross-sectional: 3) providing data on 2046 participants in total (sample size range: 14-240 participants). Relapse was defined as a return of psychotic symptoms (n = 20), a return of symptoms requiring hospitalization (n = 2) and a return of symptoms or hospitalization (n = 1). Adult stressful life events were defined as life events occurring after the onset of psychosis. Stressful life events included but were not limited to adult trauma, bereavement, financial problems and conflict. Eighteen studies found a significant positive association between adult stressful life events and psychotic relapse and five studies found a non-significant association. We conclude that adult stressful life events, occurring after psychosis onset, appear to be associated with psychotic relapse.
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Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis.
Davies, C, Segre, G, Estradé, A, Radua, J, De Micheli, A, Provenzani, U, Oliver, D, Salazar de Pablo, G, Ramella-Cravaro, V, Besozzi, M, et al
The lancet. Psychiatry. 2020;(5):399-410
Abstract
BACKGROUND Prenatal and perinatal insults are implicated in the aetiopathogenesis of psychotic disorders but the consistency and magnitude of their associations with psychosis have not been updated for nearly two decades. The aim of this systematic review and meta-analysis was to provide a comprehensive and up-to-date synthesis of the evidence on the association between prenatal or perinatal risk and protective factors and psychotic disorders. METHODS In this systematic review and meta-analysis, we searched the Web of Science database for articles published up to July 20, 2019. We identified cohort and case-control studies examining the association (odds ratio [OR]) between prenatal and perinatal factors and any International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) non-organic psychotic disorder with a healthy comparison group. Other inclusion criteria were enough data available to do the analyses, and non-overlapping datasets. We excluded reviews, meta-analyses, abstracts or conference proceedings, and articles with overlapping datasets. Data were extracted according to EQUATOR and PRISMA guidelines. Extracted variables included first author, publication year, study type, sample size, type of psychotic diagnosis (non-affective psychoses or schizophrenia-spectrum disorders, affective psychoses) and diagnostic instrument (DSM or ICD and version), the risk or protective factor, and measure of association (primary outcome). We did random-effects pairwise meta-analyses, Q statistics, I2 index, sensitivity analyses, meta-regressions, and assessed study quality and publication bias. The study protocol was registered at PROSPERO, CRD42017079261. FINDINGS 152 studies relating to 98 risk or protective factors were eligible for analysis. Significant risk factors were: maternal age younger than 20 years (OR 1·17) and 30-34 years (OR 1·05); paternal age younger than 20 years (OR 1·31) and older than 35 years (OR 1·28); any maternal (OR 4·60) or paternal (OR 2·73) psychopathology; maternal psychosis (OR 7·61) and affective disorder (OR 2·26); three or more pregnancies (OR 1·30); herpes simplex 2 (OR 1·35); maternal infections not otherwise specified (NOS; OR 1·27); suboptimal number of antenatal visits (OR 1·83); winter (OR 1·05) and winter to spring (OR 1·05) season of birth in the northern hemisphere; maternal stress NOS (OR 2·40); famine (OR 1·61); any famine or nutritional deficits in pregnancy (OR 1·40); maternal hypertension (OR 1·40); hypoxia (OR 1·63); ruptured (OR 1·86) and premature rupture (OR 2·29) of membranes; polyhydramnios (OR 3·05); definite obstetric complications NOS (OR 1·83); birthweights of less than 2000 g (OR 1·84), less than 2500 g (OR 1·53), or 2500-2999 g (OR 1·23); birth length less than 49 cm (OR 1·17); small for gestational age (OR 1·40); premature birth (OR 1·35), and congenital malformations (OR 2·35). Significant protective factors were maternal ages 20-24 years (OR 0·93) and 25-29 years (OR 0·92), nulliparity (OR 0·91), and birthweights 3500-3999 g (OR 0·90) or more than 4000 g (OR 0·86). The results were corrected for publication biases; sensitivity and meta-regression analyses confirmed the robustness of these findings for most factors. INTERPRETATION Several prenatal and perinatal factors are associated with the later onset of psychosis. The updated knowledge emerging from this study could refine understanding of psychosis pathogenesis, enhance multivariable risk prediction, and inform preventive strategies. FUNDING None.
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Nutritional Deficiencies and Clinical Correlates in First-Episode Psychosis: A Systematic Review and Meta-analysis.
Firth, J, Carney, R, Stubbs, B, Teasdale, SB, Vancampfort, D, Ward, PB, Berk, M, Sarris, J
Schizophrenia bulletin. 2018;(6):1275-1292
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Abstract
OBJECTIVE Diet is increasingly recognized as a potentially modifiable factor influencing the onset and outcomes of psychiatric disorders. Whereas, previous research has shown long-term schizophrenia is associated with various nutritional deficiencies, this meta-analysis aimed to determine the prevalence and extent of nutritional deficits in first-episode psychosis (FEP). METHOD A search of electronic databases conducted in July 2017 identified 28 eligible studies, examining blood levels of 6 vitamins and 10 minerals across 2612 individuals: 1221 individuals with FEP and 1391 control subjects. Meta-analyses compared nutrient levels in FEP to nonpsychiatric controls. Clinical correlates of nutritional status in patient samples were systematically reviewed. RESULTS Significantly lower blood levels of folate (N = 6, n = 827, g = -0.624, 95% confidence interval [CI] = -1.176 to -0.072, P = .027) and vitamin D (N = 7, n = 906, g = -1.055, 95% CI = -1.99 to -0.119, P = .027) were found in FEP compared to healthy controls. Synthesis of clinical correlates found both folate and vitamin D held significant inverse relationships with psychiatric symptoms in FEP. There was also limited evidence for serum level reductions of vitamin C (N = 2, n = 96, g = -2.207, 95% CI = -3.71 to -0.71, P = .004). No differences were found for other vitamins or minerals. CONCLUSIONS Deficits in vitamin D and folate previously observed in long-term schizophrenia appear to exist from illness onset, and are associated with worse symptomology. Further research must examine the direction and nature of these relationships (ie, mediator, moderator, or marker) with clinical status in FEP. Future trials assessing efficacy of nutrient supplementation in FEP samples should consider targeting and stratifying for baseline deficiency.
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Lipid profile disturbances in antipsychotic-naive patients with first-episode non-affective psychosis: A systematic review and meta-analysis.
Misiak, B, Stańczykiewicz, B, Łaczmański, Ł, Frydecka, D
Schizophrenia research. 2017;:18-27
Abstract
BACKGROUND Dyslipidaemia is one of the most prevalent metabolic disturbances observed in schizophrenia patients and has been largely attributed to the effects of poor lifestyle habits and adverse effects of antipsychotic treatment. However, less is known whether patients with first-episode non-affective psychosis (FENP) present subthreshold indices of dyslipidaemia. Therefore, we tested the hypothesis whether subclinical lipid profile alterations occur already in antipsychotic-naïve FENP patients. METHODS In this systematic review and meta-analysis we adhered to the PRISMA guidelines and searched PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition from database inception to Dec 12, 2016, for case-control studies measuring the levels of total cholesterol, low- and high-density lipoproteins (LDL and HDL) and triglycerides in patients with FENP and controls. W calculated effect size (ES) estimates as Hedges' g and pooled data using random- or fixed-effects models depending on heterogeneity. Our study was registered in the PROSPERO database (CRD42016051732). RESULTS Out of 2466 records identified, 19 studies representing 1803 participants were finally included in our systematic review and meta-analysis. Pooled analysis revealed that FENP patients had significantly lower levels of total cholesterol [ES=-0.16 (95% CI: -0.27, -0.06), p=0.003], LDL [ES=-0.13 (95% CI: -0.24, -0.01), p=0.034] and HDL [ES=-0.27 (95% CI: -0.49, -0.05), p=0.018] as well as significantly higher levels of triglycerides [ES=0.22 (95% CI: 0.11, 0.32), p<0.001] compared to controls. After removing single studies in sensitivity analysis, ES estimate for LDL levels was insignificant. CONCLUSIONS Antipsychotic-naïve patients with FENP present subclinical dyslipidaemia. Future studies should disentangle whether our findings reflect disease-specific mechanisms.
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Cholesterol and triglyceride levels in first-episode psychosis: systematic review and meta-analysis.
Pillinger, T, Beck, K, Stubbs, B, Howes, OD
The British journal of psychiatry : the journal of mental science. 2017;(6):339-349
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BackgroundThe extent of metabolic and lipid changes in first-episode psychosis (FEP) is unclear.AimsTo investigate whether individuals with FEP and no or minimal antipsychotic exposure show lipid and adipocytokine abnormalities compared with healthy controls.MethodWe conducted a meta-analysis of studies examining lipid and adipocytokine parameters in individuals with FEP and no or minimal antipsychotic exposure v. a healthy control group. Studies reported fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and leptin levels.ResultsOf 2070 citations retrieved, 20 case-control studies met inclusion criteria including 1167 patients and 1184 controls. Total cholesterol and LDL cholesterol levels were significantly decreased in patients v. controls, corresponding to an absolute reduction of 0.26 mmol/L and 0.15 mmol/L respectively. Triglyceride levels were significantly increased in the patient group, corresponding to an absolute increase of 0.08 mmol/L. However, HDL cholesterol and leptin levels were not altered in patients v. controls.ConclusionsTotal and LDL cholesterol levels are reduced in FEP, indicating that hypercholesterolaemia in patients with chronic disorder is secondary and potentially modifiable. In contrast, triglycerides are elevated in FEP. Hypertriglyceridaemia is a feature of type 2 diabetes mellitus, therefore this finding adds to the evidence for glucose dysregulation in this cohort. These findings support early intervention targeting nutrition, physical activity and appropriate antipsychotic prescription.
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Antiglucocorticoid and related treatments for psychosis.
Garner, B, Phillips, LJ, Bendall, S, Hetrick, SE
The Cochrane database of systematic reviews. 2016;(1):CD006995
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BACKGROUND Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in the development and relapse of psychotic disorders. Elevated cortisol secretion has been positively linked with symptom severity in people with psychosis. Antiglucocorticoid and related drugs that target the HPA axis may be useful for the treatment of individuals with psychosis. OBJECTIVES 1. To determine the effects of antiglucocorticoid and related drugs for the treatment of psychosis, when used alone or in combination with antipsychotic medication.2. To determine whether the effects of these medications differs between those in a prodromal phase or first episode of psychosis, and those with more established illness. SEARCH METHODS We searched the Cochrane Schizophrenia Group's Trials Register (August 2009 and April 2014). SELECTION CRITERIA Randomised controlled trials (RCTs) comparing antiglucocorticoid and related drugs compared to placebo (either as a sole treatment or as an adjunct to atypical antipsychotics, typical antipsychotics, antidepressants or other combination treatment) for people with a primary diagnosis of a psychotic disorder, or for individuals at high risk of developing a psychotic disorder. DATA COLLECTION AND ANALYSIS Review authors independently selected trials, assessed methodological quality and extracted data. We used a fixed-effect meta-analysis. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) and standardised mean differences (SMDs) with 95% CIs for continuous measures. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table. MAIN RESULTS We included 11 studies that randomly assigned 509 people with schizophrenia, schizoaffective disorder or psychotic depression. No trials were conducted in patients at their first episode of psychotic illness and none included populations at high risk for developing psychosis. Our pre-stated outcomes of interest were mental state, global state, general functioning, adverse effects and quality of life.Two trials compared antiglucocorticoid drugs (mifepristone) versus placebo as sole treatment. Limited data from one trial showed no difference in the proportion responding to mifepristone when mental state was assessed immediately post intervention using the Brief Psychiatric Rating Scale (BPRS) (n = 5, 1 RCT, MD -5.20, 95% CI -17.91 to 7.51; very low-quality evidence); depressive symptoms (Hamilton Rating Scale for Depression (HAMD) total) were also similar between groups (n = 5, 1 RCT, MD 1.67, 95% CI -16.44 to 19.78; very low-quality evidence). However, a significant difference favoured treatment at short-term follow-up for global state (30% reduction in total BPRS, n = 221, 1 RCT, RR 0.58, 95% CI 0.38 to 0.89; low-grade quality evidence). This effect was also seen for short-term positive psychotic symptoms (50% reduction in BPRS positive symptom subscale, n = 221, 1 RCT, RR 0.60, 95% CI 0.43 to 0.84; low-grade quality evidence). Participants receiving mifepristone experienced a similar overall number of adverse effects as those receiving placebo (n = 226, 2 RCTs, RR 0.92, 95% CI 0.77 to 1.09; moderate-quality evidence). No data on general functioning or quality of life were available.One trial compared an antiglucocorticoid, dehydroepiandrosterone (DHEA), as an adjunct to atypical antipsychotic treatment to adjunctive placebo. Data for main outcomes of interest were of low quality, and analysis of useable data showed no significant effects of treatment on mental state or adverse effects. Data on global state, general functioning and quality of life were not available.Data from six trials comparing antiglucocorticoid drugs as an adjunct to combination treatment versus adjunctive placebo showed no significant differences between groups in mean endpoint scores for overall psychotic symptoms (n = 171, 6 RCTs, SMD 0.01, 95% CI - 0.29 to 0.32) or positive psychotic symptoms (n = 151, 5 RCTs, SMD -0.07, 95% CI - 0.40 to 0.25). Data from three trials showed no differences between groups in mean endpoint scores for negative symptoms (n = 94, 3 RCTs, MD 2.21, 95% CI -0.14 to 4.55). One study found improvements in global state that were similar between groups (n = 30, 1 RCT, RR 0.58, 95% CI 0.32 to 1.06; very low-quality evidence). In this comparison, pooled results showed that antiglucorticoids caused a greater overall number of adverse events (n = 199, 7 RCTs, RR 2.66, 95% CI 1.33 to 5.32; moderate quality evidence), but no quality of life data were available. AUTHORS' CONCLUSIONS Good evidence is insufficient to conclude whether antiglucocorticoid drugs provide effective treatment for psychosis. Some global state findings suggest a favourable effect for mifepristone, and a few overall adverse effect findings favour placebo. Additional large randomised controlled trials are needed to justify findings.
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Atypical antipsychotics for psychosis in adolescents.
Kumar, A, Datta, SS, Wright, SD, Furtado, VA, Russell, PS
The Cochrane database of systematic reviews. 2013;(10):CD009582
Abstract
BACKGROUND Schizophrenia often presents in adolescence, but current treatment guidelines are based largely on studies of adults with psychosis. Over the past decade, the number of studies on treatment of adolescent-onset psychosis has increased. The current systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis. OBJECTIVES To investigate the effects of atypical antipsychotic medications in adolescents with psychosis. We reviewed in separate analyses various comparisons of atypical antipsychotic medications with placebo or a typical antipsychotic medication or another atypical antipsychotic medication or the same atypical antipsychotic medication but at a lower dose. SEARCH METHODS We searched the Cochrane Schizophrenia Group Register (October 2011), which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies and contacted study authors and relevant pharmaceutical companies to ask for more information. SELECTION CRITERIA We included all relevant randomised controlled trials (RCTs) that compared atypical antipsychotic medication with placebo or another pharmacological intervention or with psychosocial interventions, standard psychiatric treatment or no intervention in children and young people aged 13 to 18 years with a diagnosis of schizophrenia, schizoaffective disorder, acute and transient psychoses or unspecified psychosis. We included studies published in English and in other languages that were available in standardised databases. DATA COLLECTION AND ANALYSIS Review authors AK and SSD selected the studies, rated the quality of the studies and performed data extraction. For dichotomous data, we estimated risk ratios (RRs) with 95% confidence intervals (CIs) using a fixed-effect model. When possible, for binary data presented in the 'Summary of findings' table, we calculated illustrative comparative risks. We summated continuous data using the mean difference (MD). Risk of bias was assessed for included studies. MAIN RESULTS We included 13 RCTs, with a total of 1112 participants. We found no data on service utilisation, economic outcomes, behaviour or cognitive response. Trials were classified into the following groups. 1. Atypical antipsychotics versus placebo: Only two studies compared one atypical antipsychotic medication with placebo. In one study, the number of non-responders treated with olanzapine was not different from the number treated with placebo (1 RCT, n = 107, RR 0.84, 95% CI 0.65 to 1.10); however, significantly more (57% vs 32%) people left the study early (1 RCT, n = 107, RR 0.56, 95% CI 0.36 to 0.87) from the placebo group compared with the olanzapine group. With regard to adverse effects, young people treated with aripiprazole had significantly lower serum cholesterol compared with those given placebo (1 RCT, n = 302, RR 3.77, 95% CI 1.88 to 7.58). 2. Atypical antipsychotics versus typical antipsychotics: When the findings of all five trials comparing atypical antipsychotic medications with a typical antipsychotic medication were collated, no difference in the mean end point Brief Psychiatric Rating Scale (BPRS) score was noted between the two arms (5 RCTs, n = 236, MD -1.08, 95% CI -3.08 to 0.93). With regard to adverse effects, the mean end point serum prolactin concentration was much higher than the reference range for treatment with risperidone, olanzapine and molindone in one of the studies. However, fewer adolescents who were receiving atypical antipsychotic medications left the study because of adverse effects (3 RCTs, n = 187, RR 0.65, 95% CI 0.36 to 1.15) or for any reason (3 RCTs, n = 187, RR 0.62, 95% CI 0.39 to 0.97).3. One atypical antipsychotic versus another atypical antipsychotic: The mean end point BPRS score was not significantly different for people who received risperidone compared with those who received olanzapine; however, the above data were highly skewed. Overall no difference was noted in the number of people leaving the studies early because of any adverse effects between each study arm in the three studies comparing olanzapine and risperidone (3 RCTs, n = 130, RR 1.15, 95% CI 0.44 to 3.04). Specific adverse events were not reported uniformly across the six different studies included in this section of the review; therefore it was difficult to do a head-to-head comparison of adverse events for different atypical antipsychotic medications.4. Lower-dose atypical antipsychotic versus standard/higher-dose atypical antipsychotic: Three studies reported comparisons of lower doses of the atypical antipsychotic medication with standard/higher doses of the same medication. One study reported better symptom reduction with a standard dose of risperidone as compared with a low dose (1 RCT, n = 257, RR -8.00, 95% CI -13.75 to -2.25). In another study, no difference was reported in the number of participants not achieving remission between the group receiving 10 mg/d and those who received 30 mg/d of aripiprazole (1 RCT, n = 196, RR 0.84, 95% CI 0.48 to 1.48). Similarly in the other study, authors reported no statistically significant difference in clinical response between the two groups receiving lower-dose (80 mg/d) and higher-dose (160 mg/d) ziprasidone, as reflected by the mean end point BPRS score (1 RCT, n = 17, MD -4.40, 95% CI -19.20 to 10.40). AUTHORS' CONCLUSIONS No convincing evidence suggests that atypical antipsychotic medications are superior to typical medications for the treatment of adolescents with psychosis. However, atypical antipsychotic medications may be more acceptable to young people because fewer symptomatic adverse effects are seen in the short term. Little evidence is available to support the superiority of one atypical antipsychotic medication over another, but side effect profiles are different for different medications. Treatment with olanzapine, risperidone and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidaemia. Adolescents may respond better to standard-dose as opposed to lower-dose risperidone, but for aripiprazole and ziprasidone, lower doses may be equally effective. Future trials should ensure uniform ways of reporting.
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Changes in weight and metabolic parameters during treatment with antipsychotics and metformin: do the data inform as to potential guideline development? A systematic review of clinical studies.
Bushe, CJ, Bradley, AJ, Doshi, S, Karagianis, J
International journal of clinical practice. 2009;(12):1743-61
Abstract
BACKGROUND Changes in weight and metabolic parameters have been commonly reported in patients with schizophrenia. Metformin has been evaluated in clinical studies to prevent or reduce weight gain and changes in metabolic parameters in non-diabetic subjects. We undertook a systematic review of the efficacy and safety of metformin in reducing weight gain and metabolic abnormalities in non-diabetic subjects with schizophrenia or bipolar disorder taking antipsychotic medication to establish if these data could potentially drive guideline development. METHODS Medical databases were searched using terms including 'antipsychotic', 'atypical antipsychotic agent', 'antipsychotic agents', 'antipsychotic-drug' and 'metformin' and 'weight'. Studies reporting weight and/or metabolic outcomes in non-diabetic subjects with schizophrenia and bipolar disorder were included regardless of methodological type and subject age. RESULTS Nine randomised double-blind studies and two open cohort studies evaluating metformin and changes in weight in trials up to 16 weeks were identified. In all, 495 participants received antipsychotics (mostly olanzapine), and three studies were in subjects aged < 18 years. The adult studies predominantly utilised non-Caucasian subjects with chronic schizophrenia. Weight and lifestyle intervention programmes were provided to all cohorts in eight studies, which confounded interpretation of the data. In ten studies, the addition of metformin to antipsychotic treatment was associated with either significantly attenuated weight gain or weight loss compared with control groups. Nine studies measured various glucose parameters. In four studies, subjects prescribed metformin had significantly improved glucose parameters relative to controls. The two studies of metformin in patients with first-episode schizophrenia demonstrated the largest improvement in weight and glucose parameters. CONCLUSIONS Metformin may have some value in reducing or preventing weight gain and changes in metabolic parameters during treatment with antipsychotic medication particularly in first-episode psychosis; however, it has been predominantly studied short-term and in non-Caucasian populations. A number of new trials are due to report data 2009-2013 to aid definitive interpretation of the role of metformin. Further longer-term studies are warranted before definitive guidelines can be established.