To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure firstname.lastname@example.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis.
Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0–11 years), and late (12–17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use.
The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord.
Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.
Tobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis.
The sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use.
After controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1–3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day (p = 0.003; AOR 1.7; 95% CI [1.2–2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset (β = −2.3; p ⩽ 0.001; 95% CI [−3.7 to −0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0–1.8]); however, these results were no longer significant after controlling for cannabis use.
Tobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.
Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample.
Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of ‘Genetic’ models (solely fitted with PRS-SZ), ‘Environmental’ models (solely fitted with each environmental stressor), ‘Independent’ models (with PRS-SZ and each environmental factor), and ‘Interaction’ models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models.
There were no genes-environment associations. PRS-SZ was associated with positive dimensions (β = 0.092, R2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension.
This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.
Increasing evidence shows that impaired neuroplasticity and high inflammation play a crucial role in the pathophysiology of schizophrenia. Prospective studies demonstrated that patients with high inflammation usually have a poor treatment response and clinical practice learns that negative symptoms are challenging to treat. The predictive value of biomarkers for negative symptoms in patients with schizophrenia has sparsely been explored.
Here, we investigated whether biomarkers are associated with negative symptoms at baseline, and whether biomarkers could predict negative symptoms after six years in patients with schizophrenia.
We investigated serum biomarkers in an epidemiological study on schizophrenia (N, baseline=110; N, follow-up=65). Negative symptoms were measured using the Positive and Negative Syndrome Scale. Biomarkers (N=189) were measured with a multi-analyte profiling platform and analysed using linear regression models, adjusted for site, age, gender, ethnicity, anti-inflammatory agents, smoking, cardiovascular disease and diabetes, and adjusted for multiple comparisons (q, Benjamini-Hochberg procedure).
In particular, decreased platelet-derived growth factor (PDGF) (responsible for proliferation of oligodendrocytes) was associated with more negative symptoms at baseline and follow-up (figure). Several other biomarkers associated with inflammation, neuroplasticity and metabolism correlated with the severity of negative symptoms cross-sectionally and/or prospectively. Figure. Biomarkers for Negative Symptoms in Schizophrenia.
Although our sample size at follow-up was limited, we feel that these analyses contribute to further research of possible predictive biomarkers for negative symptoms in schizophrenia. During the conference we will elaborate our findings with applied machine learning techniques which might shed more light on the predictive value of biomarkers for negative symptoms in schizophrenia.
Childhood trauma is associated with an elevated risk for psychosis, but the psychological mechanisms involved remain largely unclear. This study aimed to investigate emotional and psychotic stress reactivity in daily life as a putative mechanism linking childhood trauma and clinical outcomes in individuals at ultra-high-risk (UHR) for psychosis.
Experience sampling methodology was used to measure momentary stress, affect and psychotic experiences in the daily life of N = 79 UHR individuals in the EU-GEI High Risk Study. The Childhood Trauma Questionnaire was used to assess self-reported childhood trauma. Clinical outcomes were assessed at baseline, 1- and 2-year follow-up.
The association of stress with positive (β = −0.14, p = 0.010) and negative affect (β = 0.11, p = 0.020) was modified by transition status such that stress reactivity was greater in individuals who transitioned to psychosis. Moreover, the association of stress with negative affect (β = 0.06, p = 0.019) and psychotic experiences (β = 0.05, p = 0.037) was greater in individuals exposed to high v. low levels of childhood trauma. We also found evidence that decreased positive affect in response to stress was associated with reduced functioning at 1-year follow-up (B = 6.29, p = 0.034). In addition, there was evidence that the association of childhood trauma with poor functional outcomes was mediated by stress reactivity (e.g. indirect effect: B = −2.13, p = 0.026), but no evidence that stress reactivity mediated the association between childhood trauma and transition (e.g. indirect effect: B = 0.14, p = 0.506).
Emotional and psychotic stress reactivity may be potential mechanisms linking childhood trauma with clinical outcomes in UHR individuals.
This meta-analysis on peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder (MDD) examined which compounds change following psychopharmacological treatment.
The Embase, PubMed and PsycINFO databases were systematically searched for longitudinal studies reporting measurements of blood compounds in drug-naïve first-episode schizophrenia or MDD.
For this random-effects meta-analysis, we retrieved a total of 31 studies comprising 1818 schizophrenia patients, and 14 studies comprising 469 MDD patients. Brain-derived neurotrophic factor (BDNF) increased following treatment in schizophrenia (Hedges' g (g): 0.55; 95% confidence interval (CI) 0.39–0.70; p < 0.001) and MDD (g: 0.51; CI 0.06–0.96; p = 0.027). Interleukin (IL)-6 levels decreased in schizophrenia (g: −0.48; CI −0.85 to −0.11; p = 0.011), and for MDD a trend of decreased IL-6 levels was observed (g: −0.39; CI −0.87 to 0.09; p = 0.115). Tumor necrosis factor alpha (TNFα) also decreased in schizophrenia (g: −0.34; CI −0.68 to −0.01; p = 0.047) and in MDD (g: −1.02; CI −1.79 to −0.25; p = 0.009). Fasting glucose levels increased only in schizophrenia (g: 0.26; CI 0.07–0.44; p = 0.007), but not in MDD. No changes were found for C-reactive protein, IL-1β, IL-2 and IL-4.
Psychopharmacological treatment has modulating effects on BDNF and TNFα in drug-naïve first-episode patients with either schizophrenia or MDD. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune dysfunctions.
Investigation of treatments that effectively treat adults with post-traumatic stress disorder from childhood experiences (Ch-PTSD) and are well tolerated by patients is needed to improve outcomes for this population.
The purpose of this study was to compare the effectiveness of two trauma-focused treatments, imagery rescripting (ImRs) and eye movement desensitisation and reprocessing (EMDR), for treating Ch-PTSD.
We conducted an international, multicentre, randomised clinical trial, recruiting adults with Ch-PTSD from childhood trauma before 16 years of age. Participants were randomised to treatment condition and assessed by blind raters at multiple time points. Participants received up to 12 90-min sessions of either ImRs or EMDR, biweekly.
A total of 155 participants were included in the final intent-to-treat analysis. Drop-out rates were low, at 7.7%. A generalised linear mixed model of repeated measures showed that observer-rated post-traumatic stress disorder (PTSD) symptoms significantly decreased for both ImRs (d = 1.72) and EMDR (d = 1.73) at the 8-week post-treatment assessment. Similar results were seen with secondary outcome measures and self-reported PTSD symptoms. There were no significant differences between the two treatments on any standardised measure at post-treatment and follow-up.
ImRs and EMDR treatments were found to be effective in treating PTSD symptoms arising from childhood trauma, and in reducing other symptoms such as depression, dissociation and trauma-related cognitions. The low drop-out rates suggest that the treatments were well tolerated by participants. The results from this study provide evidence for the use of trauma-focused treatments for Ch-PTSD.
Neurocognitive abnormalities are prevalent in both first episode schizophrenia patients and in ultra high risk (UHR) patients.
To compare verbal fluency performance at baseline in UHR in patients that did and did not make the transition to psychosis.
Baseline verbal fluency performance in UHR-patients (n = 47) was compared to match first episode patients (n = 69) and normal controls (n = 42).
Verbal fluency (semantic category) scores in UHR-patients did not differ significantly from the score in first episode schizophrenia patients. Both the UHR group (p < 0.003) and the patient group (p < 0.0001) performed significantly worse than controls. Compared to the non-transition group, the transition group performed worse on verbal fluency, semantic category (p < 0.006) at baseline.
Verbal fluency (semantic category) is disturbed in UHR-patients that make the transition to psychosis and could contribute to an improved prediction of transition to psychosis in UHR-patients.
In the case of a first episode of psychosis among members of different associations of families of mentally ill people, little is known about their priorities and how satisfied they are with the help provided to them. A survey was conducted in five European family associations. Respondents emphasized the need for early (ambulant) intervention through outreach with very practical goals directed at creating stability and social functioning. About one-third of the respondents are unsatisfied or very unsatisfied. The highest percentage of unsatisfied respondents was in the following five areas of care: advice on how to handle specific problems; help with preserving or regaining social functioning; help with regaining structure and routine; information; prompt assistance preferably in patientˈs own environment. The agreement of these findings with findings from earlier studies underlines the importance of suggesting specific changes in the delivery of care.
This study examines the relationship between duration of untreated psychosis (DUP) and long-term symptomatic and social outcome in 205 patients with schizophrenia, whose parents are member of a consumer organisation. We found only a tendency that longer DUP was related to negative symptoms, but no relation to other outcome domains. The results of this study do not support antipsychotic intervention at the earliest sign of psychosis in order to ‘protect the brain’.
Psychiatric services providing care for patients and their families confronted with a first psychotic episode need to be sensitive towards patients’ and families’ preferences. Ten patients, ten family members and ten professional caregivers composed a list of 42 preferences in the treatment for a first psychotic episode. In total 99 patients, 100 family members and 263 professional caregivers evaluated these preferences, thus producing an order of priorities. There appears to be considerable agreement among the groups of respondents regarding their top ten priorities, especially concerning information on diagnosis and medication. However, we found important differences between groups of respondents. The results suggest that in psychiatric services great attention should be given to psycho-education and early outpatient intervention.
Parents, especially mothers, have a critical role in initiating psychiatric treatment for their child with first-episode schizophrenia. Knowledge of attitudes of mothers towards the illness of their child prior to psychiatric treatment and towards the start of treatment is essential for the development of interventions for reducing duration of untreated psychosis (DUP). In the present study, mothers (n = 61) of consecutively admitted patients with recent-onset schizophrenic disorders were interviewed about: their views on the nature of the symptoms at first occurrence of psychotic symptoms in their child and views on the main reason for psychiatric treatment; their perception of problems in initiating psychiatric treatment; and suggestions they might have for getting treatment started at an earlier point in time. About 57% of the mothers did not think that their child had a psychosis at first occurrence of psychotic symptoms. Most of the mothers who immediately thought that their child suffered from a psychotic disorder supposed that this disorder was caused by use of street drugs. About one-third (32.8%) of the mothers thought that the reluctance of patients to acknowledge that they needed help was the major obstacle in initiating psychiatric treatment. More than half of the mothers perceived factors related to the delivery of professional care as problems in initiating psychiatric treatment. Given the reluctance of patients to accept treatment, these problems further complicate the initiating of treatment. Mothers emphasize that a more active approach by professional caregivers could reduce treatment delay.
Patients with schizophrenia have lower IQ as compared to the general population. Furthermore, cognitive decline has been observed even before the onset of the first episode psychosis. Whether premorbid functioning and IQ also predict long-term remission status is not yet known.
1057 patients with schizophrenia and related disorders were included in GROUP project. Premorbid Adjustment Scale (PAS), IQ and Positive and Negative Symptom Scale (PANSS) were obtained at inclusion. After 6 years 691 patients were re-examined. On 530 patients we were able to determine remission status using the PANSS remission tool. Patients were divided into two groups; those who were in remission (Rem) and those who were not (NR). Groups were compared on PAS and IQ using independent sample t-tests groups.
Analyses revealed that patients who dropped out during the follow-up of 6 years had lower IQ, and higher PANSS scores as compared to those who were remained in the study. After 6 years 58% of patients were in remission. Remission status after 6 years was associated with IQ and premorbid adjustment in childhood and adolescence at inclusion.
Poorer premorbid adjustment and lower IQ at baseline are associated with non-remission after 6 years. This suggests that in order to improve the course and outcome of schizophrenia, one should aim to detect and intervene well before the first psychotic symptoms arise.
It has been suggested that mixing alcohol with energy drinks (AMED) and other caffeinated beverages may alter the awareness of intoxication. The proposed reduction in subjective intoxication, also called “the masking effect”, may have serious consequences by increasing the likelihood of engaging in potentially dangerous activities such as driving while intoxicated.
The aim of this meta-analysis was to determine if mixing alcohol with caffeinated beverages alters subjective intoxication.
A literature search was conducted (August 21st, 2012) to collect all studies measuring subjective intoxication after administration of AMED, or other caffeinated alcoholic drinks compared to alcohol only. To this extent, PubMed and Embase were searched using the key words “alcohol”, “caffeine”, “energy drinks” and “intoxication”. The studies were critically reviewed and, where possible, included in a meta-analysis in order to determine whether masking exists after mixing alcohol with caffeinated beverages.
Twelve studies were identified of which 8 could be used for the meta-analysis. When including higher caffeine doses (4 mg/kg) the meta-analysis revealed no significant masking effect (p= 0.477). Similarly, when including lower caffeine doses (2 mg/kg) no significant masking effect was found (p=0 .434). Despite the large range of caffeine content (46 - 383 mg) and alcohol levels (0.03% - 0.12% BAC) investigated, caffeine had no effect on the correct judgment of subjective intoxication.
Mixing alcohol with energy drink or other caffeinated beverages does not alter subjective intoxication.
Nonadherence to antipsychotic medication is highly prevalent in patients with schizophrenia and has a deleterious impact on the course of the illness. This review seeks to determine the interventions that were examined in the past decade to improve adherence rates.
The literature between 2000 and 2009 was searched for randomized controlled trials which compared a psychosocial intervention with another intervention or with treatment as usual in patients with schizophrenia.
Fifteen studies were identified, with a large heterogeneity in design, adherence measures and outcome variables. Interventions that offered more sessions during a longer period of time, and especially those with a continuous focus on adherence, seem most likely to be successful, as well as pragmatic interventions that focus on attention and memory problems. The positive effects of adapted forms of Motivational Interviewing found in earlier studies, such as compliance therapy, have not been confirmed.
Nonadherence remains a challenging problem in schizophrenia. The heterogeneity of factors related to nonadherence calls for individually tailored approaches to promote adherence. More evidence is required to determine the effects of specific interventions.
The incidence of psychotic disorders is increased among men and culminates in adolescence. After menopause, there is a second peak in the incidence among women. It has therefore been suggested that sex steroids, such as oxytocin and testosterone, may confer decreased or increased risks for psychotic disorders.
To investigate differences in peripheral oxytocin and testosterone plasma levels in patients with a first psychotic episode, their unaffected siblings and healthy controls.
Plasma hormone assays of oxytocin and testosterone were obtained from 85 patients with a psychotic disorder, 27 of their unaffected siblings and 59 healthy controls. Sex-hormone binding globulin (SHBG) was collected to calculate the free androgen index (FAI; testosterone/SHBG), a broad indicator of androgen status. We analyzed group differences in hormone levels, as well as associations with demographic and illness parameters.
There were no significant differences in plasma oxytocin levels or FAI across groups. Adjusted for age, smoking, time of blood draw and BMI, we found a significant group difference in plasma testosterone levels in males (F(6,72)= 2.8; p<0.05), not in females. This effect was primarily caused by significantly higher mean plasma testosterone levels in antipsychotic-naive men (n=15) compared to their unaffected brothers (p<0.01) and healthy controls (p<0.05).
This study contradicts previous findings of decreased testosterone and oxytocin levels in patients with a psychotic disorder. Increased plasma testosterone in antipsychotic-naive male patients may reflect social distrust and paranoid thinking. It further underlines a potential mechanism of antipsychotic medication of normalizing androgen activity.
An association between Toxoplasma gondii (T. gondii) and schizophrenia has been shown by a meta-analysis showing a significant Odds Ratio (OR) of 2.7. Currently, several studies have looked at the association between T. gondii and other psychiatric disorders as well, rendering exploration of diagnostic specificity possible. Furthermore, questions remain on the timing and nature of the infection.
A systematic search was performed to identify relevant studies of all major psychiatric disorders versus healthy controls in relation to T. gondii infection. Methodological quality, heterogeneity and risk of bias were assessed.
A total of 2866 studies were found, from which 51 studies were finally included. Significant ORs were found for Schizophrenia, Bipolar Disorder, OCD and Addiction, but not for Major Depression. Further exploration of the association between T. gondii and schizophrenia, yielded a significant association of seropositivity before onset of psychosis and with high antibody titers. A decline of the association was found when baseline exposure in the healthy control population increased.
These findings suggest that T. gondii infection is not merely associated with psychosis and that in schizophrenia a reactivation of a latent T. gondii infection occurs. Several hypotheses remain open about the nature of this association.
Several factors may contribute to duration of untreated psychosis (DUP): patient-delay, referral-delay and treatment-delay caused by mental health care services (MHS-delay). In order to find the most effective interventions to reduce DUP, it is important to know what factors in these pathways to care contribute to DUP.
To examine the relationship of the constituents of treatment delay, migration status and urbanicity.
In first episode psychotic patients (n = 182) from rural, urban and highly urbanized areas, DUP, migration status and pathways to care were determined.
Mean DUP was 53.6 weeks (median 8.9, SD=116.8). Patient-delay was significantly longer for patients from highly urbanized areas and for first generation immigrants. MHS-delay was longer for patients who were treated already by MHS for other diagnoses.
Specific interventions are needed focusing on patients living in highly urbanized areas and first generation immigrants in order to shorten patient delay. MHS should improve early detection of psychosis in patients already in treatment for other diagnosis.
Schizophrenia is associated with an increased risk of sudden cardiac death, traditionally attributed to prolonged QTc interval and cardiovascular risk factors such as metabolic syndrome. However, defective ion channels are also implicated in schizophrenia. This applies as well for Brugada syndrome (BrS), a rare hereditary cardiac disorder associated with an increased risk of cardiac arrhythmias, which can been provoked by various drugs, including psychotropic.
To screen whether an increased prevalence of suspect Brugada ECG is present in patients with recent onset schizophrenia.
273 subjects with recent onset schizophrenia admitted between 2006 and 2012 and 306 healthy controls, underwent an ECG. All persons who had an ECG suspect for BrS were asked to undergo a provocation test to diagnose/exclude BrS. We checked whether patients had deceased during follow-up.
20/273 patients (7.3%) and 5/306 healthy controls (1.6%) showed an ECG suspect for BrS, with a Relative risk (RR) of 4.8 (p<0.001). Thus far 12 provocation tests have been performed, confirming BrS in three patients (1.1%). Ten patients had deceased during follow-up, of which two due to sudden cardiac death. Patients and controls didn’t differ significantly on average QTc interval.
Conclusion: This study shows that a considerable subset of patients with recent onset schizophrenia have an ECG suspect of Brugada Syndrome, confirming results in a population with chronic schizophrenia (Blom 2014). This may imply that there is a common pathophysiologic mechanism involved in both disorders. Screening for Brugada Syndrome in schizophrenia is relevant to prevent sudden cardiac death.
Multimorbidity may impose an overwhelming burden on patients with psychosis and is affected by gender and age. Our aim is to study the independent role of familial liability to psychosis as a risk factor for multimorbidity.
We performed the study within the framework of the Genetic Risk and Outcome of Psychosis (GROUP) project. Overall, we compared 1024 psychotic patients, 994 unaffected siblings and 566 controls on the prevalence of 125 lifetime diseases, and 19 self-reported somatic complaints. Multimorbidity was defined as the presence of two or more complaints/diseases in the same individual. Generalized linear mixed model (GLMM) were used to investigate the effects of gender, age (adolescent, young, older) and familial liability (patients, siblings, controls) and their interactions on multimorbidity.
Familial liability had a significant effect on multimorbidity of either complaints or diseases. Patients had a higher prevalence of multimorbidity of complaints compared to siblings (OR 2.20, 95% CI 1.79–2.69, P < 0.001) and to controls (3.05, 2.35–3.96, P < 0.001). In physical health multimorbidity, patients (OR 1.36, 95% CI 1.05–1.75, P = 0.018), but not siblings, had significantly higher prevalence than controls. Similar finding were observed for multimorbidity of lifetime diseases, including psychiatric diseases. Significant results were observed for complaints and disease multimorbidity across gender and age groups.
Multimorbidity is a common burden, significantly more prevalent in patients and their unaffected siblings. Familial liability to psychosis showed an independent effect on multimorbidity; gender and age are also important factors determining multimorbidity.