Pneumonia Risk, Antipsychotic Dosing, and Anticholinergic Burden in Schizophrenia.

Importance: Antipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use and incident pneumonia, it remains unclear to what degree antipsychotic use is associated with increased risk of pneumonia, whether dose-response associations exist, and what agents are specifically associated with incident pneumonia. Objective: To estimate pneumonia risk associated with specific antipsychotics and examine whether polytherapy, dosing, and receptor binding properties are associated with pneumonia in patients with schizophrenia. Design, Setting, and Participants: This cohort study identified patients with schizophrenia or schizoaffective disorder (hereafter, schizophrenia) aged 16 years or older from nationwide Finnish registers from 1972 to 2014. Data on diagnoses, inpatient care, and specialized outpatient care were obtained from the Hospital Discharge Register. Information on outpatient medication dispensing was obtained from the Prescription Register. Study follow-up was from 1996 to 2017. Data were analyzed from November 4, 2022, to December 5, 2023. Exposures: Use of specific antipsychotic monotherapies; antipsychotics modeled by dosage as low (<0.6 of the World Health Organization defined daily dose [DDD] per day), medium (0.6 to <1.1 DDDs per day), or high dose (≥1.1 DDDs per day); antipsychotic polypharmacy; and antipsychotics categorized according to their anticholinergic burden as low, medium, and high. Main Outcomes and Measures: The primary outcome was hospitalization for incident pneumonia. Pneumonia risk was analyzed using adjusted, within-individual Cox proportional hazards regression models, with no antipsychotic use as the reference. Results: The study included 61 889 persons with schizophrenia (mean [SD] age, 46.2 [16.0] years; 31 104 men [50.3%]). During 22 years of follow-up, 8917 patients (14.4%) had 1 or more hospitalizations for pneumonia and 1137 (12.8%) died within 30 days of admission. Compared with no antipsychotic use, any antipsychotic use overall was not associated with pneumonia (adjusted hazard ratio [AHR], 1.12; 95% CI, 0.99-1.26). Monotherapy use was associated with increased pneumonia risk compared with no antipsychotic use (AHR, 1.15 [95% CI, 1.02-1.30]; P = .03) in a dose-dependent manner, but polytherapy use was not. When categorized by anticholinergic burden, only the use of antipsychotics with a high anticholinergic burden was associated with pneumonia (AHR, 1.26 [95% CI, 1.10-1.45]; P < .001). Of specific drugs, high-dose quetiapine (AHR, 1.78 [95% CI, 1.22-2.60]; P = .003), high- and medium-dose clozapine (AHR, 1.44 [95% CI, 1.22-1.71]; P < .001 and AHR, 1.43 [95% CI, 1.18-1.74]; P < .001, respectively), and high-dose olanzapine (AHR, 1.29 [95% CI, 1.05-1.58]; P = .02) were associated with increased pneumonia risk. Conclusions and Relevance: Results of this cohort study suggest that in patients with schizophrenia, antipsychotic agents associated with pneumonia include not only clozapine (at dosages ≥180 mg/d) but also quetiapine (≥440 mg/d) and olanzapine (≥11 mg/d). Moreover, monotherapy antipsychotics and antipsychotics with high anticholinergic burden are associated with increased pneumonia risk in a dose-dependent manner. These findings call for prevention strategies aimed at patients with schizophrenia requiring high-risk antipsychotics.

Antipsychotic Use and Risk of Breast Cancer in Women With Severe Mental Illness: Replication of a Nationwide Nested Case-Control Database Study.

BACKGROUND AND HYPOTHESIS: Breast cancer is more prevalent in women with severe mental illness than in the general population, and use of prolactin-increasing antipsychotics may be a contributing factor. STUDY DESIGN: A nested case-control study was conducted using the Swedish nationwide registers (inpatient/outpatient care, sickness absence, disability pension, prescribed drugs, cancers). All women aged 18-85 years with schizophrenia/schizoaffective/other nonaffective psychotic disorder/bipolar disorder and breast cancer (cases) were matched for age, primary psychiatric diagnosis, and disease duration with five women without cancer (controls). The association between cumulative exposure to prolactin-increasing/prolactin-sparing antipsychotics and breast cancer was analyzed using conditional logistic regression, adjusted for comorbidities and co-medications. STUDY RESULTS: Among 132 061 women, 1642 (1.24%) developed breast cancer between 2010 and 2021, at a mean age of 63.3 ±â€…11.8 years. Compared with 8173 matched controls, the odds of breast cancer increased in women with prior exposure to prolactin-increasing antipsychotics for 1-4 years (adjusted odds ratio [aOR] = 1.20, 95% confidence interval [CI] = 1.03-1.41), and for ≥ 5 years (aOR = 1.47, 95%CI = 1.26-1.71). There were no increased or decreased odds of breast cancer with exposure to prolactin-sparing antipsychotics of either 1-4 years (aOR = 1.17, 95%CI = 0.98-1.40) or ≥5 years (aOR = 0.99, 95%CI = 0.78-1.26). The results were consistent across all sensitivity analyses (ie, according to different age groups, cancer types, and primary psychiatric diagnosis). CONCLUSIONS: Although causality remains uncertain, exposure to prolactin-elevating antipsychotics for ≥ 1 year was associated with increased odds of breast cancer in women with severe mental illness. When prescribing antipsychotics, a shared decision-making process should consider individual risk factors for breast cancer.

Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study.

Genomic prediction of antipsychotic dose and polypharmacy has been difficult, mainly due to limited access to large cohorts with genetic and drug prescription data. In this proof of principle study, we investigated if genetic liability for schizophrenia is associated with high dose requirements of antipsychotics and antipsychotic polypharmacy, using real-world registry and biobank data from five independent Nordic cohorts of a total of N = 21,572 individuals with psychotic disorders (schizophrenia, bipolar disorder, and other psychosis). Within regression models, a polygenic risk score (PRS) for schizophrenia was studied in relation to standardized antipsychotic dose as well as antipsychotic polypharmacy, defined based on longitudinal prescription registry data as well as health records and self-reported data. Meta-analyses across the five cohorts showed that PRS for schizophrenia was significantly positively associated with prescribed (standardized) antipsychotic dose (beta(SE) = 0.0435(0.009), p = 0.0006) and antipsychotic polypharmacy defined as taking ≥2 antipsychotics (OR = 1.10, CI = 1.05-1.21, p = 0.0073). The direction of effect was similar in all five independent cohorts. These findings indicate that genotypes may aid clinically relevant decisions on individual patients´ antipsychotic treatment. Further, the findings illustrate how real-world data have the potential to generate results needed for future precision medicine approaches in psychiatry.

Effect of severity of depression on augmentation of antidepressant medication in young adults with depression.

BACKGROUND: Antipsychotics (AP) have been used to augment antidepressant (AD) medication in treatment-resistant depression. In this study we examined factors (including severity of depression and initial antidepressant) affecting AP augmentation, as well as which APs were initiated as augmentation in young adults. METHODS: Data were extracted from Finnish nationwide registers. Of persons aged 18-29 years diagnosed with a depression during 2004-2017 we focused on incident AD users (who initiated AD 6 months before and after the diagnosis) whose severity level of depression was recorded (N = 21,966). AP augmentation was studied during 1 year after diagnosis of depression. Persons diagnosed with severe depression with psychotic features (n = 1486) were excluded from main analyses and analyzed separately. RESULTS: Overall, 8.4% of new antidepressant users initiated AP augmentation. Risk of augmentation increased with severity of depression as 3.9%, 5.8%, and 14.0% of persons with mild, moderate, and severe depression, respectively, initiated augmentation. Male sex, comorbid anxiety and personality disorders, substance abuse and selfharm/suicide attempt were positively associated with augmentation. Compared to citalopram, use of tricyclic antidepressant, paroxetine and venlafaxine were associated with increased risk of augmentation, while use of bupropion was associated with a decreased risk. Quetiapine and risperidone were the most common APs used in augmentation. Among persons with severe depression with psychotic features, use of sertraline was associated with AP augmentation, whereas use of fluoxetine decreased risk of augmentation. CONCLUSIONS: Use of APs as augmentation of AD therapy was common in severe depression. Comorbidities had only a small effect to augmentation, but selection of initial AD was more closely associated to risk of augmentation. Interestingly, use of bupropion decreased risk of augmentation, which warrants further studies, as well as the decrease in risk of augmentation when fluoxetine in case of psychotic depression was used.

The role of sociodemographic and clinical factors in the initiation and discontinuation of attention deficit hyperactivity disorder medication among young adults in Sweden.

Introduction: Long-term medication use is a recommended treatment for attention-deficit/hyperactivity disorder (ADHD), however, discontinuation is common. Non-medical factors which might influence initiation and discontinuation are understudied. Therefore, we investigated how different sociodemographic factors and comorbidities were associated with the initiation and discontinuation of ADHD medication use among young adults. Methods and results: We conducted a population-based prospective cohort study using individually linked administrative register data, in which we included all individuals residing in Sweden, between the age of 19 and 29 who were first diagnosed with ADHD between January 2006 and December 2016 (n = 59224). ADHD medication initiation was defined as the first prescription of ADHD medication in the period from 3 months before to 6 months after the cohort entry date. Those who initiated ADHD medication were followed up for medication use until discontinuation, death/emigration, or until 2019. Logistic and Cox regression models were used to investigate the associations between sociodemographics, health-related predictors and initiation, as well as discontinuation. Overall, 48.7% of the 41399 individuals initiated ADHD medication, most often methylphenidate (87%). Among the initiators, 15462 (77%) discontinued medication use during the follow-up (median time: 150 days). After mutually adjusting all other predictors, initiation was positively associated with older age, male sex, higher level of education, and negatively associated with living at home with parents, immigrant status, being unemployed during the year before inclusion, being on disability pension, having autism, substance use, schizophrenia-spectrum disorders, other mental disability/developmental disorders, cardiovascular diseases or previous accidents. Discontinuation was positively associated with being born abroad, living in big cities, being unemployed during the year before inclusion, having cancer, and negatively associated with a higher educational level, having depression, anxiety or stress-related disorder, autism spectrum disorder or diabetes. Conclusion: Besides medical factors, sociodemographics, such as educational attainment and immigrant status might also play a role in the initiation and discontinuation of ADHD medication use among young adults newly diagnosed with ADHD.

Safety of Antipsychotic Polypharmacy Versus Monotherapy in a Nationwide Cohort of 61,889 Patients With Schizophrenia.

OBJECTIVES: The authors sought to study the safety of antipsychotic polypharmacy compared with monotherapy in specific dosage categories. METHODS: Patients with schizophrenia (N=61,889; median follow-up, 14.8 years [IQR=7.4-22.0]) were identified from the Finnish nationwide inpatient care register and followed up over the period 1996-2017. Antipsychotic polypharmacy was compared with monotherapy in seven dosage categories (<0.4, 0.4-<0.6, 0.6-<0.9, 0.9-<1.1, 1.1-<1.4, 1.4-<1.6, and ≥1.6 defined daily doses [DDDs] per day) in terms of risk of severe physical morbidity, indicated by nonpsychiatric and cardiovascular hospitalizations (adjusted hazard ratio). Within-individual analysis was used in an effort to eliminate selection bias. RESULTS: The mean age of the cohort was 46.7 years (SD=16.0), and 50.3% (N=31,104) were men. Among patients who had used both monotherapy and polypharmacy, the risk of nonpsychiatric hospitalization was significantly lower during polypharmacy use at all total dosage categories above 1.1 DDDs/day with differences up to -13% than during monotherapy use of the same dosage category (for 1.1-<1.4 DDDs/day, adjusted hazard ratio=0.91, 95% CI=0.87-0.95; for 1.4-<1.6 DDDs/day, adjusted hazard ratio=0.91, 95% CI=0.86-0.96; and for ≥1.6 DDDs/day, adjusted hazard ratio=0.87, 95% CI=0.84-0.89). The risk of cardiovascular hospitalization was significantly lower for polypharmacy at the highest total dosage category (-18%, adjusted hazard ratio=0.82, 95% CI=0.72-0.94). The results from the comparisons between monotherapy and no use and between polypharmacy and no use were in line with the primary comparison of polypharmacy and monotherapy within the same individual. Comparison of any polypharmacy use with any monotherapy use showed no significant difference for nonpsychiatric or cardiovascular hospitalization. CONCLUSIONS: The results show that antipsychotic monotherapy is not associated with a lower risk of hospitalization for severe physical health problems when compared with antipsychotic polypharmacy. Treatment guidelines should not encourage use of monotherapy instead of antipsychotic polypharmacy without any existing evidence on the safety issues.

Associations between antipsychotic use, substance use and relapse risk in patients with schizophrenia: real-world evidence from two national cohorts.

BACKGROUND: Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid substance use disorder (SUD) is very sparse, and non-existent on the prevention of the development of SUDs in patients with schizophrenia. AIMS: To compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risk of developing an initial SUD, and psychiatric hospital admission and SUD-related hospital admission among patients with an SUD. METHOD: Two independent national cohorts including all persons diagnosed with schizophrenia (N = 45 476) were followed up for 22 (Finland: 1996-2017) and 11 (Sweden: 2006-2016) years. Risk of developing an SUD was calculated with between-individual models, and risks of psychiatric and SUD-related hospital admission were calculated with within-individual models, using Cox regression and adjusted hazard ratios (aHRs) for using versus not using certain antipsychotics. RESULTS: For patients with schizophrenia without an SUD, clozapine use (Finland: aHR 0.20, 95% CI 0.16-0.24, P < 0.001; Sweden: aHR 0.35, 95% CI 0.24-0.50, P < 0.001) was associated with lowest risk of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (aHR 0.54, 95% CI 0.44-0.66) in Sweden, and third lowest risk (aHR 0.47, 95% CI 0.42-0.53) in Finland. Risk of relapse (psychiatric hospital admission and SUD-related hospital admission) were lowest for clozapine, antipsychotic polytherapy and long-acting injectables in both countries. Results were consistent across both countries. CONCLUSIONS: Clozapine and antipsychotic polytherapy are most strongly associated with reduced risk of developing SUDs among patients with schizophrenia, and with lower relapse rates among patients with both diagnoses.

Allopurinol, dipyridamole and calcium channel blockers in the treatment of bipolar disorder - A nationwide cohort study.

BACKGROUND: Improved treatments for bipolar disorder (BD) are needed. Drug repurposing aims to find novel targets for drugs that have been used for other indications. This study investigated the risk of psychiatric hospitalization associated with use of calcium-channel blockers (CCBs; dihydropyridines, diltiazem, verapamil) and adenosine modulators (allopurinol, dipyridamole) in BD in within-individual design. METHODS: Individuals diagnosed with BD (ICD-10: F30-F31) were identified from the inpatient, specialized outpatient, sickness absence, and disability pension registers during 1996-2018 in Finland (N = 60,045). The main outcome was hospitalization due to affective symptoms (ICD-10: F30-F39). Within-individual models in stratified Cox regression were used and adjusted hazard ratios (aHR) with 95 % confidence intervals (CIs) reported. RESULTS: Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR 0.83, 95 % CI 0.78-0.88) when all CCBs were analyzed together. Of specific CCBs, use of diltiazem (0.71, 0.55-0.91) and dihydropyridines (0.83, 0.78-0.89) were associated with a decreased risk but verapamil was not (0.93, 0.73-1.19). Use of adenosine modulators in general was associated with a decreased risk of hospitalizations due to affective symptoms (0.87, 0.79-0.96). Both allopurinol (0.85, 0.74-0.97) and dipyridamole (0.89, 0.78-1.00) were associated with a marginally decreased risk. Thiazide diuretic use as a negative control was not associated with the risk of hospitalization due to affective symptoms (0.97, 0.83-1.13). LIMITATIONS: Due to the observational nature of this study, causation cannot be confirmed. CONCLUSIONS: Dihydropyridines and diltiazem were associated with a decreased risk of psychiatric hospitalization in bipolar disorder. Results for allopurinol and dipyridamole were inconclusive.

Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors.

People with schizophrenia die 15-20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random-effects meta-analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all-cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific-cause mortality. Publication bias, subgroup and meta-regression analyses, and quality assessment (Newcastle-Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all-cause mortality was increased in people with schizophrenia versus any non-schizophrenia control group (RR=2.52, 95% CI: 2.38-2.68, n=79), with the largest risk in first-episode (RR=7.43, 95% CI: 4.02-13.75, n=2) and incident (i.e., earlier-phase) schizophrenia (RR=3.52, 95% CI: 3.09-4.00, n=7) versus the general population. Specific-cause mortality was highest for suicide or injury-poisoning or undetermined non-natural cause (RR=9.76-8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79-7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio-cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All-cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001-0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all-cause and suicide-related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide-related mortality risk in incident schizophrenia samples. All-cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all-cause mortality (RR=1.62, 95% CI: 1.47-1.80, n=3). Antipsychotics were protective against all-cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59-0.84, n=11), with largest effects for second-generation long-acting injectable anti-psychotics (SGA-LAIs) (RR=0.39, 95% CI: 0.27-0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34-0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39-0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44-0.63, n=4). Antipsychotics were also protective against natural cause-related mortality, yet first-generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural-cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long-term maintenance antipsychotic treatment and appropriate/earlier use of SGA-LAIs and clozapine could reduce this mortality gap.

Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland.

BACKGROUND: Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics. METHODS: We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions. FINDINGS: For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis. INTERPRETATION: Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine. FUNDING: The Finnish Ministry of Social Affairs and Health and Academy of Finland.

Automated multi-dose dispensing in persons with and without Alzheimer's disease-impacts on pharmacotherapy.

PURPOSE: We investigated the drug use before and after transition to automated multi-dose dispensing (MDD) service among persons with Alzheimer's disease (AD) and compared whether the changes were similar in persons without AD. METHODS: The register-based Finnish nationwide MEDALZ cohort includes 70,718 community-dwelling persons diagnosed with AD during 2005-2011. Each person who initiated MDD was matched in both groups with a comparison person without MDD by age, gender and for persons with AD, also time since AD diagnosis at the start of MDD. The study cohort included 15,604 persons with AD in MDD and 15,604 no-MDD, and 5224 persons without AD in MDD and 5224 no-MDD. Point prevalence of drug use was assessed every 3 months, from 1 year before to 2 years after the start of MDD and compared between persons in MDD to those who did not have MDD. RESULTS: MDD was started on average 2.9 (SD 2.1) years after AD diagnosis. At the start of MDD, the prevalence of drug use increased especially for antipsychotics, antidepressants, opioids, paracetamol and use of ≥ 10 drugs among persons with and without AD. Prevalence of benzodiazepine use (from 12% 12 months before to 17% at start of MDD), memantine (from 29 to 46%) and ≥ 3 psychotropics (from 3.2 to 6.0%) increased among persons with AD. Decreasing trend was observed for benzodiazepine-related drugs, urinary antispasmodics and non-steroidal anti-inflammatory drugs. CONCLUSION: MDD seems to be initiated when use of psychotropics is initiated and the number of drugs increases.

Antipsychotic use and risk of breast cancer in women with schizophrenia: a nationwide nested case-control study in Finland.

BACKGROUND: Breast cancer is more common in female patients with schizophrenia than in the general population. It is not known whether treatment with prolactin-increasing antipsychotics contributes to increased odds of breast cancer. METHODS: We used Finnish nationwide registers of hospital treatment, prescription drug purchases, and cancer diagnoses to do a nested case-control study. Of women with schizophrenia, those with breast cancer (cases) were matched by age and duration of illness with five women without cancer (controls). Cases and controls were aged 18-85 years and exclusion criteria were any previous cancer diagnoses, receipt of organ transplant, mastectomy, or diagnosis of HIV. The main analysis was the association between cumulative exposure to prolactin-increasing drugs and breast cancer. The analyses were done with conditional logistic regression, by adjusting for comorbid conditions and concomitant medications. Ethnicity data were not available. FINDINGS: Of 30 785 women diagnosed with schizophrenia between 1972 and 2014, 1069 were diagnosed with breast cancer between Jan 1, 2000, and Dec 31, 2017. Compared with 5339 matched controls, 1-4 years cumulative exposure (adjusted odds ratio [OR] 0·95, 95% CI 0·73-1·25) or 5 or more years exposure (adjusted OR 1·19, 0·90-1·58) to prolactin-sparing antipsychotics (including clozapine, quetiapine, or aripiprazole) was not associated with an increased risk of breast cancer in comparison with minimal exposure (<1 year). When compared with less than 1 year of exposure to prolactin-increasing antipsychotics (all other antipsychotics), 1-4 years of exposure was not associated with an increased risk, but exposure for 5 or more years was associated with an increased risk (adjusted OR 1·56 [1·27-1·92], p<0·001). The risk for developing lobular adenocarcinoma associated with long-term use of prolactin-increasing antipsychotics (adjusted OR 2·36 [95% CI 1·46-3·82]) was higher than that of developing ductal adenocarcinoma (adjusted OR 1·42 [95% CI 1·12-1·80]). INTERPRETATION: Long-term exposure to prolactin-increasing, but not to prolactin-sparing, antipsychotics is significantly associated with increased odds of breast cancer. Monitoring prolactinemia and addressing hyperprolactinemia is paramount in women with schizophrenia being treated with prolactin-increasing antipsychotics. FUNDING: Finnish Ministry of Social Affairs and Health.

Risk Factors, Incidence, and Outcomes of Neuroleptic Malignant Syndrome on Long-Acting Injectable vs Oral Antipsychotics in a Nationwide Schizophrenia Cohort.

INTRODUCTION: Long-acting injectable antipsychotics (LAIs) are associated with multiple positive outcomes in psychosis, but it is unclear whether LAIs are associated with worse outcomes if neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect, occurs. METHODS: We used nationwide and nationally representative databases of healthcare encounters in Finland to study the incidence and outcome predictors of NMS in patients diagnosed with schizophrenia/schizoaffective disorder between January 01, 1972 and December 31, 2017. Using a nested case-control design, we also explored differences by antipsychotic formulation (LAI vs oral antipsychotic [OAP]) and class (first-generation antipsychotic [FGA] vs second-generation antipsychotic [SGA]). RESULTS: One hundred seventy-two NMS cases and 1441 sex-, age-, and diagnosis-matched controls were included (age = 58.8 ± 13.1 years, males = 59.9%). Incidence of NMS was 1.99 (1.98-2.00) per 10 000 person-years. The likelihood of developing NMS did not differ by antipsychotic formulation (adjusted odds ratio [aOR]: 0.89, 95% confidence intervals [95% CI]: 0.59-1.33, for LAIs vs OAPs) or class (FGA-OAP vs SGA-OAP [aOR: 1.08, 95% CI: 0.66-1.76], FGA-LAI [aOR: 0.89, 95% CI: 0.52-1.53], SGA-LAI [aOR: 1.35, 95% CI: 0.58-3.12]). NMS risk factors included antipsychotic treatment change: increased number (odds ratios [OR]: 5.00, 95% CI: 2.56-9.73); decreased number/switch (OR: 2.43, 95% CI: 1.19-4.96); higher antipsychotic dose (>2DDDs-OR: 3.15, 95% CI: 1.61-6.18); co-treatment with anticholinergics (OR: 2.26, 95% CI: 1.57-3.24), lithium (OR: 2.16, 95% CI: 1.30-3.58), benzodiazepines (OR: 2.02, 95% CI: 1.44-3.58); and comorbid cardiovascular disease (OR: 1.73, 95% CI: 1.22-2.45). Within 30 days, 4.7% of cases with NMS died (15.1% within 1 year) without differences by antipsychotic formulation. NMS reoccurred in 5 of 119 subjects (4.2%), after a median = 795 (range = 77-839) days after rechallenge with antipsychotics. CONCLUSION: NMS remains a potentially life-threatening risk, yet these results should further contribute to mitigate concerns about LAI safety regarding NMS onset or outcomes, including mortality.

Molecular signaling pathways underlying schizophrenia.

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA-related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists - which have shown beneficial effects in an experimental Adcyap1-/- mouse model for schizophrenia - could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.

Incidence of schizophrenia and influence of prenatal and infant exposure to viral infectious diseases.

OBJECTIVE: There is conflicting evidence in recent literature about whether the incidence of schizophrenia is increasing or decreasing. A role for prenatal and early childhood viral infections in the aetiology of schizophrenia has also been debated. We examined the incidence of schizophrenia and the catatonic subtype of schizophrenia over a 30-year period in Finland. We also investigated whether the incidence rate of the catatonic subtype of schizophrenia was linked to changes in exposure to viral infection (polio and measles) during the prenatal or infant period. METHODS: Persons with schizophrenia were identified from the Hospital Discharge Register. Cumulative incidence of schizophrenia from 1956 to 1989 in 4 age groups was calculated with follow-up from 1972 to 2014. Annual rates of polio and measles were derived from nationwide registers. The association between log-transformed polio and measles incidence and incidence of schizophrenia, and specifically catatonic schizophrenia, were analysed using linear models. RESULTS: Cumulative incidence of schizophrenia among individuals born 1956-1989 decreased by 23% (from 13 to 10 cases per 1000 live births). The decline was the most prominent in those with onset of schizophrenia diagnosed 16-25 years of age (-41%). The incidence of catatonic schizophrenia declined by 90% over three decades, and there was a significant association between annual polio incidence during the birth year and incidence of catatonic schizophrenia. CONCLUSIONS: The results indicate that the incidence of schizophrenia in Finland has declined for individuals born between 1956 and 1989, and that the decline of catatonic schizophrenia may be partially attributable to eradication of polio.

Morbidity and mortality in schizophrenia with comorbid substance use disorders.

OBJECTIVE: Schizophrenia is highly comorbid with substance use disorders (SUD) but large epidemiological cohorts exploring the prevalence and prognostic significance of SUD are lacking. Here, we investigated the prevalence of SUD in patients with schizophrenia in Finland and Sweden, and the effect of these co-occurring disorders on risks of psychiatric hospitalization and mortality. METHODS: 45,476 individuals with schizophrenia from two independent national cohort studies, aged <46 years at cohort entry, were followed during 22 (1996-2017, Finland) and 11 years (2006-2016, Sweden). We first assessed SUD prevalence (excluding smoking). Then, we performed Cox regression on risk of psychiatric hospitalization and all-cause and cause-specific mortality in SUD compared with those without SUD. RESULTS: The prevalence of SUD ranged from 26% (Finland) to 31% (Sweden). Multiple drug use (n = 4164, 48%, Finland; n = 3268, 67%, Sweden) and alcohol use disorders (n = 3846, 45%, Finland; n = 1002, 21%, Sweden) were the most prevalent SUD, followed by cannabis. Any SUD comorbidity, and particularly multiple drug use and alcohol use, were associated with 50% to 100% increase in hospitalization (aHR any SUD: 1.53, 95% CI = 1.46-1.61, Finland; 1.83, 1.72-1.96, Sweden) and mortality (aHR all-cause mortality: 1.65, 95% CI = 1.50-1.81, Finland; 2.17, 1.74-2.70, Sweden) compared to individuals without SUD. Elevated mortality risks were observed especially for suicides and other external causes. All results were similar across countries. CONCLUSION: Co-occurring SUD, and particularly alcohol and multiple drug use, are associated with high rates of hospitalization and mortality in schizophrenia. Preventive interventions should prioritize detection and tailored treatments for these comorbidities, which often remain underdiagnosed and untreated.

Association of recent hospitalisation with antidepressant initiation among community dwellers with Alzheimer's disease.

OBJECTIVES: Antidepressant are commonly prescribed to persons with cognitive disorders to treat depressive and other neuropsychiatric symptoms despite the inconclusive evidence on their effectiveness on this indication. We studied whether recent hospitalisation was associated with antidepressant initiation in people with Alzheimer's disease (AD). METHODS: The register-based Finnish nationwide Medication use and Alzheimer's disease cohort includes community-dwelling persons diagnosed with AD during 2005-2011 in Finland (n = 70,718). This study was restricted to people who initiated antidepressant use after AD diagnosis and had no active cancer treatment and schizophrenia or bipolar disorder diagnoses. We performed a nested case-control study with antidepressant initiators as cases. A matched noninitiator (sex, age and AD duration), was identified for each initiator (15,360 matched pairs). Recent hospitalisation was defined as hospital discharge within the past 14 days of initiation. RESULTS: Antidepressant initiators were four times more likely (adjusted odds ratio: 4.41, 95% confidence interval: 4.06-4.80) to have been hospitalised within the past 2 weeks before initiation (21.2%, n = 3250) than matched noninitiators (5.4%, n = 831) and the duration of hospital stay was significantly longer among initiators. Dementia was the most common main discharge diagnosis among both initiators (43.8%, n = 1423) and noninitiators (24.8%, n = 206). CONCLUSION: Recent hospitalisation was strongly associated with antidepressant initiation in persons with AD. Further studies are needed to investigate whether this is due to neuropsychiatric symptoms leading to hospital admission, inpatient care triggering or worsening neuropsychiatric symptoms or other indications. Nonpharmacological treatments for neuropsychiatric symptoms should be prioritised and the threshold for prescribing antidepressants should be high.

Adenosine modulators and calcium channel blockers as add-on treatment for schizophrenia.

Relapses remain common among individuals with schizophrenia indicating a need for improved treatments. Creating a completely new drug molecule is expensive and time consuming, and therefore drug repurposing should be considered. Aim of this study was to investigate the risk of psychiatric rehospitalization associated with use of adenosine modulators (AMs) and calcium channel blockers (CCBs) in schizophrenia. Individuals diagnosed with schizophrenia (N = 61,889) in inpatient care between 1972-2014 in Finland were included. The follow-up lasted from 1996 to 2017. Main exposures were use of AMs (allopurinol and dipyridamole) and CCBs (dihydropyridines, diltiazem, and verapamil). Thiazide diuretics were used as a negative control. Within-individual models in stratified Cox regression were used and adjusted hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Use of AMs was associated with a reduced risk of psychiatric rehospitalization on drug class level (HR 0.74, 95% CI 0.65-0.84, P < 0.0001), as well as on the level of individual drugs (allopurinol HR 0.82, 95% CI 0.70-0.97, P = 0.02; dipyridamole HR 0.65, 95% CI 0.55-0.77, P < 0.0001). Use of CCBs was associated with a reduced risk of psychiatric rehospitalization on drug class level (HR 0.81, 95% CI 0.77-0.86, P < 0.0001). From the different CCBs, only exposure to dihydropyridines was associated with a reduced risk (HR 0.79, 95% CI 0.74-0.84, P < 0.0001). No effect was observed for the negative control, thiazide diuretics (HR 0.96, 0.90-1.02, P = 0.20). The effects of dipyridamole and dihydropyridines were more pronounced among younger persons and combination of AMs, and CCBs was associated with a lower risk than either drug class as monotherapy. These results indicate a need for randomized controlled trials of these drugs.