Psychotic Depression Research Articles

Gene expression of kynurenine pathway enzymes in depression and following electroconvulsive therapy.

This study aimed to investigate changes in mRNA expression of the kynurenine pathway (KP) enzymes tryptophan 2, 3-dioxygenase (TDO), indoleamine 2, 3-dioxygenase 1 and 2 (IDO1, IDO2), kynurenine aminotransferase 1 and 2 (KAT1, KAT2), kynurenine monooxygenase (KMO) and kynureninase (KYNU) in medicated patients with depression (n = 74) compared to age- and sex-matched healthy controls (n = 55) and in patients with depression after electroconvulsive therapy (ECT). Associations with mood score (24-item Hamilton Depression Rating Scale, HAM-D24), plasma KP metabolites and selected glucocorticoid and inflammatory immune markers known to regulate KP enzyme expression were also explored. HAM-D24 was used to evaluate depression severity. Whole blood mRNA expression was assessed using quantitative real-time polymerase chain reaction. KAT1, KYNU and IDO2 were significantly reduced in patient samples compared to control samples, though results did not survive statistical adjustment for covariates or multiple comparisons. ECT did not alter KP enzyme mRNA expression. Changes in IDO1 and KMO and change in HAM-D24 score post-ECT were negatively correlated in subgroups of patients with unipolar depression (IDO1 only), psychotic depression and ECT responders and remitters. Further exploratory correlative analyses revealed altered association patterns between KP enzyme expression, KP metabolites, NR3C1 and IL-6 in depressed patients pre- and post-ECT. Further studies are warranted to determine if KP measures have sufficient sensitivity, specificity and predictive value to be integrated into stress and immune associated biomarker panels to aid patient stratification at diagnosis and in predicting treatment response to antidepressant therapy.

Predictors of attrition during acute pharmacotherapy of psychotic depression in a clinical trial

Little is known about factors that contribute to attrition in clinical trials of the pharmacotherapy of psychotic depression. The purpose of this study was to identify factors associated with attrition during acute pharmacotherapy in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II) clinical trial. Sociodemographic and clinical variables were assessed at baseline in 269 men and women, aged 18–85 years, who were treated with up to 12 weeks of open-label sertraline plus olanzapine. Univariate analyses examined the association of baseline variables with overall non-completion, as well as reasons for non-completion. Logistic regression was used to model the relationship of the significant univariate predictors with non-completion and its reasons. Seventy-four (27.5 %) participants did not complete the acute treatment phase of STOP-PD II. Male gender, younger age, inpatient status, higher Clinical Global Impression (CGI) severity of illness, and higher severity of psychomotor disturbance were associated with non-completion in univariate analyses. In regression models, higher CGI severity of illness score was the only significant independent predictor of non-completion, explained by withdrawal of consent. Our findings have implications for the retention of persons with psychotic depression in clinical trials.

Patterns in paternal and maternal filicide: A comparative analysis of filicide cases in Turkey.

Filicide is the act of a parent killing their own offspring. Previous studies indicate that there are both commonalities and distinctions between filicides committed by mothers and fathers. The main objective of this study was to compare maternal and paternal filicide with a major focus on clinical and sociodemographic features of perpetrators, incident details, and victims. Filicide cases were examined at the bedded unit of the Expertise Department of Observation of the Council of Forensic Medicine that were referred by the Turkish Ministry of Justice. A total of 51 perpetrators and 57 victims were analyzed from June 2014 to December 2023. The perpetrators were daily face-to-face interviews by psychiatry and forensic medicine physicians. There were significant differences in sociodemographic characteristics and psychiatric conditions between maternal and paternal cases. Female perpetrators tended to be younger, unemployed, mostly targeted younger victims and used asphyxiation to kill, whereas males tended to target older victims and utilized firearms. The most common primary cause of filicide in maternal cases was "unwanted pregnancy," whereas "spousal revenge" and "anger or impulsivity" were predominant in paternal filicides. All perpetrators who were not criminally responsible were mothers, mostly diagnosed with psychotic depression. Unwanted pregnancy, psychotic depression, and postpartum psychosis should be assessed when evaluating risk for mothers, especially for infanticide. The desire for revenge on a spouse, often seen with personality disorders, impulsivity and anger, access to firearms should be screened for risk of paternal filicide, particularly in older victims. Early recognition of these factors can help in implementing prevention strategies.

AKT question relating to management of psychotic depression

AKT question relating to management of psychotic depression

AKT answer relating to management of psychotic depression

AKT answer relating to management of psychotic depression

Neuropsychological performance in women at risk of postpartum depression and postpartum psychosis.

While neuropsychological deficits are commonly observed in affective and psychotic disorders, this remains unexplored in these disorders when they occur during pregnancy and the postpartum period. A neuropsychological test battery was administered to women defined at risk of postpartum depression (PD, N = 53) because having either a current or past diagnosis of major depressive disorder, women at risk of postpartum psychosis (PP, N = 43) because of a diagnosis of bipolar disorder or schizoaffective disorder and/or a previous episode of PP and women not at risk (NR, N = 48) in the third trimester of pregnancy. Generalized and specific cognitive abilities were compared between groups. Women at risk of PP presented worse executive functions and processing speed compared to NR and worse performance compared to women at risk of PD across all cognitive domains. In addition, women at risk of PP who developed a psychiatric relapse in the first four weeks post-partum showed worse verbal learning and memory, visual memory, executive functions and processing speed in pregnancy compared to NR, whereas women at risk of PP who remained well presented neuropsychological performance that was intermediate between that of the women NR and those at risk of PP who developed symptoms. There were no differences in performance between women at risk of PD and the NR women, even if 31 women at risk of PD presented depressive symptoms at the time of cognitive assessment. Our findings in women at risk of PP align with neuropsychological findings in individuals with, or at risk of psychosis unrelated to pregnancy. In addition, initial evidence that women at risk of PP who develop a psychiatric relapse in the postpartum show a particularly poor neuropsychological performance in pregnancy suggests that this could be considered part of a phenotype for the disease and help guiding future preventive strategies in this clinical population. In women at risk of PD, the presence of depressive symptoms did not influence cognitive performance.

Pharmacotherapy profile for mothers with schizophrenia and bipolar affective disorder in a psychiatric mother–baby unit

AbstractBackgroundPharmacotherapy treatment is used to manage women with schizophrenia and bipolar affective disorder admitted to a mother–baby unit (MBU).AimThe aims of this study were (1) to examine prescribing practices for women with schizophrenia and bipolar affective disorder in an MBU, (2) to assess alignment with the Mental health care in the perinatal period: Australian clinical practice guideline and (3) to examine the classes of typical and atypical antipsychotics prescribed to mothers with schizophrenia.MethodA retrospective audit of women with schizophrenia and bipolar affective disorder admitted to a psychiatric MBU, located in Queensland, Australia, was conducted from March 2017–July 2019. The exclusion criteria included women admitted with depression, anxiety, personality disorders, and postpartum psychosis. Pharmacotherapy treatment details were extracted at commencement of admission, mid‐way through admission, and discharge. Descriptive statistics were completed. This project was exempt due to the local policy requirements that constitute research by the Gold Coast Hospital and Health Service Human Research Ethics Committee (Reference no: EX/2023/QGC/102306). The justification for this exemption was as follows: the study was deemed a quality improvement activity and complied with Chapter 2.3 of the National Statement of Ethical Conduct in Research and involved only routinely collected data.ResultsOf the 53 mothers included in the study, 29 (55%) had schizophrenia and 24 (45%) had bipolar affective disorder. In addition, 97% of women with schizophrenia received atypical antipsychotics. Five women (21%) with bipolar affective disorder (mean age = 31.60 years, standard deviation = 6.19 years) were prescribed sodium valproate, with four women given contraception. Sodium valproate or lamotrigine were prescribed to four women (67%) with bipolar affective disorder whilst breastfeeding. Of mothers prescribed lithium, 92% did not breastfeed. Overall, 44% of women involuntarily admitted received antipsychotic depot medication compared with 38% of voluntary patients. Results are discussed in relation to the national guidelines.ConclusionThis is the first naturalistic study to examine the pharmacotherapy management of postpartum women admitted to a psychiatric MBU with schizophrenia and bipolar affective disorder. The study highlights that prescribing patterns across three time points during admission were generally in alignment with Australian national guidelines.

Cognitive Function in Patients with Psychotic and Affective Disorders: Effects of Combining Pharmacotherapy with Cognitive Remediation.

Background: Cognitive impairment is a relevant problem in psychiatry and can be well assessed with a cross-diagnostic test such as the Screen for Cognitive Impairment in Psychiatry (SCIP). The aim of our pilot study is to assess cognitive impairment in acute psychiatric inpatients diagnosed with psychotic disorders, bipolar disorder and depression using the German version of the SCIP (SCIP-G). We also investigate whether cognitive dysfunction improves over the course of the inpatient treatment, where patients are offered a combination of pharmacological treatment and cognitive remediation. Methods: A total of 143 adult inpatients were included in the study. Cognitive testing was performed using two different forms of the SCIP-G. All patients received state-of-the-art pharmacotherapy and cognitive remediation using the COGPACK® software package version 6.06. Results: Based on the ICD-10 Criteria for Research, 54 patients were given an F2 diagnosis (schizophrenia and schizotypal and delusional disorders). Thirty-nine patients met the criteria for bipolar disorder (F30 and F31) and fifty for depression (F32 and F33). At baseline, a significant difference was observed between the SCIP total scores of the F2 and F32/33 patients (p < 0.001) and between the F2 and F30/31 groups (p = 0.022). At the second measurement time point, the SCIP total score showed significant improvement in all three groups (p < 0.001), and there was no statistically significant interaction between SCIP total score and diagnostic groups (p = 0.860). Conclusions: Cognitive dysfunction is present in psychiatric disorders and can be easily assessed during an inpatient hospital stay. In our sample, patients with a psychotic disorder were more cognitively impaired at baseline than patients with an affective disorder. Inpatient treatment, consisting of pharmacotherapy and cognitive remediation, improved cognitive deficits. Patients with psychotic disorders, bipolar disorder and depression showed similar improvements in cognitive performance.

Clinical and sociodemographic characteristics associated with relapse following electroconvulsive therapy for bipolar disorder.

Electroconvulsive therapy (ECT) is an effective treatment for bipolar disorder, but relapse following a successful ECT series is common. We aimed to identify clinical and sociodemographic characteristics associated with the risk of relapse following ECT in bipolar disorder. Using data from nationwide Danish registers, we identified all patients receiving their first ECT series with an indication diagnosis of bipolar disorder between 2006 and 2018. We then followed these patients for relapse, defined as either psychiatric admission or a new ECT series, for 6 months following ECT. Associations between clinical and sociodemographic characteristics and relapse were examined via multivariable Cox proportional-hazards regression, yielding adjusted hazard rate ratios (aHRR). Of the 1473 patients receiving ECT for bipolar disorder (62% females, mean age = 53 years), 34% met the relapse criterion. The following characteristics were associated with an elevated risk of relapse; age <40 (aHRR = 1.54, 95% CI = 1.05-2.26); being a pensioner (aHRR = 1.73, 95% CI = 1.29-2.32), indication diagnosis for ECT being psychotic mania (aHRR = 1.63, 95% CI = 1.16-2.28), psychotic bipolar depression (aHRR = 1.37, 95% CI = 1.06-1.80), mixed episode (aHRR = 1.51, 95% CI = 1.13-2.02), or other bipolar episodes (aHRR = 1.68, 95% CI = 1.28-2.21); and treatment with antipsychotics prior to the course of ECT (aHRR = 1.32, 95% CI = 1.04-1.67). Patients with bipolar disorder face a particularly high risk of relapse following ECT if they present with the following characteristics when initiating ECT: age <40, being a pensioner, having received treatment with an antipsychotic before initiating ECT, or having psychotic bipolar depression, psychotic mania, mixed episodes, or other bipolar episodes as the indication for ECT. These findings may guide relapse monitoring following ECT in bipolar disorder.

Exploring Therapeutic Potential: A Comprehensive Review of Novel Treatment Targets in Psychotic Depression

Exploring Therapeutic Potential: A Comprehensive Review of Novel Treatment Targets in Psychotic Depression

On the Edge of the Impossible – The Use of Multiple Monitored Electroconvulsive Therapy (MMECT) in a Patient with Severe Psychotic Depression after two Myocardial Infarctions

On the Edge of the Impossible – The Use of Multiple Monitored Electroconvulsive Therapy (MMECT) in a Patient with Severe Psychotic Depression after two Myocardial Infarctions

Substance-Induced Psychiatric Disorders, Epigenetic and Microbiome Alterations, and Potential for Therapeutic Interventions.

Substance use disorders (SUDs) are complex biopsychosocial diseases that cause neurocognitive deficits and neurological impairments by altering the gene expression in reward-related brain areas. Repeated drug use gives rise to alterations in DNA methylation, histone modifications, and the expression of microRNAs in several brain areas that may be associated with the development of psychotic symptoms. The first section of this review discusses how substance use contributes to the development of psychotic symptoms via epigenetic alterations. Then, we present more evidence about the link between SUDs and brain epigenetic alterations. The next section presents associations between paternal and maternal exposure to substances and epigenetic alterations in the brains of offspring and the role of maternal diet in preventing substance-induced neurological impairments. Then, we introduce potential therapeutic agents/approaches such as methyl-rich diets to modify epigenetic alterations for alleviating psychotic symptoms or depression in SUDs. Next, we discuss how substance use-gut microbiome interactions contribute to the development of neurological impairments through epigenetic alterations and how gut microbiome-derived metabolites may become new therapeutics for normalizing epigenetic aberrations. Finally, we address possible challenges and future perspectives for alleviating psychotic symptoms and depression in patients with SUDs by modulating diets, the epigenome, and gut microbiome.

Considering the role of estradiol in the psychoneuroimmunology of perimenopausal depression

In recent years, a burgeoning field of research has focused on women's mental health and psychiatric conditions associated with perinatal and postpartum periods. An emerging trend points to the link between hormone fluctuations during pregnancy and postpartum that have immunologic consequences in cases of perinatal depression and postpartum psychosis. The transition to menopause (or “perimenopause”) has garnered comparatively less attention, but existing studies point to the influential interaction of hormonal and immune pathways. Moreover, the role of this cross talk in perturbing neural networks has been implicated in risk for cognitive decline, but relatively less work has focused on the depressed brain during perimenopause. This brief review brings a psychoneuroimmunology lens to depression during the perimenopausal period by providing an overview of existing knowledge and suggestions for future research to intertwine these bodies of work.

The influence of age on ECT efficacy in depression, mania, psychotic depression and schizophrenia: A transdiagnostic analysis

AimECT use is variable across age groups. We aim to investigate the effect of age on ECT response among patients with depression, psychotic depression, mania and schizophrenia. MethodsOur retrospective observational study included patients from the Institute of Mental Health (Singapore) who were initiated on ECT (March 2017–February 2023). MADRS and BPRS scores were assessed 1–2 days before the first ECT and after the 6th session. The association between age group and ECT response was analyzed by ANOVA and generalized linear regression. A one-way sensitivity analysis was performed with age as a continuous variable. Results166 (15.7%) patients were “young-age (≤26 years)”, 634 (60%) patients were in the “middle-age (27–59 years)” group and 256 (24.3%) were “old-age (≥60 years)”. The association between older age and post-ECT improvement in patients with depression was significant in the categorical age analysis but it did not persist in the sensitivity analysis. No significant association between age and ECT response was noted in patients with bipolar disorder and schizophrenia as evidenced by both categorical and continuous age analyses. In a small subgroup with psychotic depression, younger patients improved significantly more than older patients post-ECT. ConclusionPatients with unipolar or bipolar depression, mania, or schizophrenia, regardless of age, respond favourably to ECT. Other associated factors such as psychomotor and psychotic symptoms, disease severity and number of failed pharmacotherapies should be considered in predicting ECT response. Younger patients with psychotic depression may respond better to ECT.

The impact of perinatal maternal mental health disorders on the child’s health

Perinatal mental disorders constitute an important health and social problem. Pre- and postnatal depression affects both the mother and her child. The most common postpartum mental health disorders include the so-called baby blues, postpartum depression and postpartum psychosis. Depression in pregnancy is associated with a greater risk of premature birth and low birth weight. Depression during pregnancy has also been linked to diabetes and preeclampsia. Furthermore, the influence of maternal mental disorders on the development of allergic diseases and neurodevelopmental disorders in the child has been proven. Perinatal depression can lead to impaired bonding between mother and child, which has a long-term impact on the child’s emotional and social development. Perinatal depression may also affect both mental development and the occurrence of somatic diseases in children. The main mental disorders observed in the children of mothers with perinatal depression include behavioural problems, destructive behaviour, anxiety disorders and insecurity. An increased risk of atopic dermatitis and recurrent upper and lower airway infections has been proven in children of depressed mothers. Considering the above, it seems obvious that the protection of the mental health of pregnant and postpartum women and children should be multifaceted and multi-tracked. Untreated depression may have long-term consequences on the child’s development.

Bipolar disorder and Lewy body dementia: case report and literature review.

Depressive episodes with psychotic symptoms are prevalent among the older adults, emphasizing the need to differentiate them from dementia with Lewy bodies (DLB), in which depressive and psychotic symptoms commonly coexist. In contrast, psychotic symptoms occur more frequently in depressive episodes of bipolar disorder (BD) than in major depressive disorder (MDD). Although MDD is a significant risk factor for dementia, studies exploring the relationship between BD and dementia are lacking. This report details the case of a 74-year-old female who experienced severe psychotic depression that led to suicide attempts during a long-term course of young-onset BD. Ultimately, she was diagnosed with DLB based on her neurocognitive symptoms and results of the neuroimaging examination. She had experienced multiple relapses in the past, predominantly characterized by depressive episodes in her old age. Notably, she had never undergone lithium treatment, which is known for its potential efficacy in preventing relapse and dementia. Recent systematic reviews and meta-analyses have suggested that patients with BD have a higher risk of dementia than the general population, and that lithium usage is associated with a reduced risk. Moreover, patients with BD have been suggested to have an elevated risk of developing Parkinson's disease (PD), and the pathophysiological relationship between BD and PD may be attributed to dopamine dysregulation resulting from multiple relapses. Future research is imperative to identify strategies for preventing dementia in patients with BD and to develop interventions for the comorbidities of BD and DLB.

Association of Problematic Internet Use With Psychotic Experiences and Depression in Adolescents: A Cohort Study.

Problematic internet use (PIU) is prevalent among adolescents. Past research suggested cross-sectional associations between PIU and psychotic experiences, but little information is available on the longitudinal association. We hypothesized that PIU in adolescence may be longitudinally associated with psychotic experiences, adjusting for confounders. We analyzed a random sample of adolescents in the Tokyo Teen Cohort to examine how PIU at ages 10 (2012-2015), 12 (2014-2017), and 16 (2019-2021) was associated with mental health issues at age 16. PIU was evaluated by the modified Compulsive Internet Use Scale, psychotic experiences by the Adolescent Psychotic-like Symptom Screener, and depression by the Short Mood and Feelings Questionnaire. We also examined the mediating role of social withdrawal. We analyzed 3171 adolescents; 151 reported psychotic experiences and 327 reported depression at age 16. Compared with the lowest tertile PIU group, the highest tertile PIU group at age 12 showed an increased adjusted risk of psychotic experiences (RD 3.3%, 95% CI 2.9%-3.7%; RR 1.65, 95% CI 1.55-1.73) and depression (RD 5.9%, 95% CI 5.5%-6.3%; RR 1.61, 95% CI 1.55-1.68) at age 16. PIU at age 16 showed analogous results, while PIU at age 10 suggested a smaller impact. Social withdrawal mediated 9.4%-29.0% of the association between PIU and psychotic experiences. PIU is longitudinally associated with psychotic experiences and depression in adolescents. Further longitudinal and intervention studies are warranted to provide robust public health implications and foster a safer digital future.

Electroconvulsive therapy in the maintenance phase of psychotic unipolar depression.

To determine whether the rates of readmissions and suicide vary in psychotic unipolar depression based on whether patients receive maintenance electroconvulsive therapy (M-ECT) following the initial series of ECT, and to examine if there is an age-dependent association. We used Swedish national registries to identify hospitalized patients with psychotic unipolar depression, treated 2008-2019 who received ECT during their hospital stay. The patients who received subsequent M-ECT within 14 days after discharge were compared with those who did not. The primary composite outcome was time to readmission due to a psychiatric disorder, suicide attempt, or suicide within 2 years from discharge. Data were analyzed using Cox regression adjusted for previous psychiatric admissions, age, sex, comorbidity, and pharmacological treatment. We also conducted a within-individual analysis using the sign-test, with patients having ≥1 hospital episode followed by M-ECT and ≥1 hospital episode without M-ECT. A total of 1873 patients were included, of which 130 received M-ECT. There was no statistically significant group difference regarding the primary outcome in the whole sample. However, when stratified by age, there was a significant difference in favor of M-ECT for patients >65 years (adjusted hazard ratio 0.55, 95% confidence interval 0.35-0.87). The within-individual analysis, including 46 patients, significantly favored M-ECT. M-ECT was not associated with a differential risk of the composite of readmission and suicide in psychotic depression. Among patients >65 years, M-ECT was significantly associated with a decreased risk of the outcome. The possibility of residual confounding cannot be excluded.

Air and Noise Pollution Exposure in Early Life and Mental Health From Adolescence to Young Adulthood

Growing evidence associates air pollution exposure with various psychiatric disorders. However, the importance of early-life (eg, prenatal) air pollution exposure to mental health during youth is poorly understood, and few longitudinal studies have investigated the association of noise pollution with youth mental health. To examine the longitudinal associations of air and noise pollution exposure in pregnancy, childhood, and adolescence with psychotic experiences, depression, and anxiety in youths from ages 13 to 24 years. This cohort study used data from the Avon Longitudinal Study of Parents and Children, an ongoing longitudinal birth cohort founded in 1991 through 1993 in Southwest England, United Kingdom. The cohort includes over 14 000 infants with due dates between April 1, 1991, and December 31, 1992, who were subsequently followed up into adulthood. Data were analyzed October 29, 2021, to March 11, 2024. A novel linkage (completed in 2020) was performed to link high-resolution (100 m2) estimates of nitrogen dioxide (NO2), fine particulate matter under 2.5 μm (PM2.5), and noise pollution to home addresses from pregnancy to 12 years of age. Psychotic experiences, depression, and anxiety were measured at ages 13, 18, and 24 years. Logistic regression models controlled for key individual-, family-, and area-level confounders. This cohort study included 9065 participants who had any mental health data, of whom (with sample size varying by parameter) 51.4% (4657 of 9051) were female, 19.5% (1544 of 7910) reported psychotic experiences, 11.4% (947 of 8344) reported depression, and 9.7% (811 of 8398) reported anxiety. Mean (SD) age at follow-up was 24.5 (0.8) years. After covariate adjustment, IQR increases (0.72 μg/m3) in PM2.5 levels during pregnancy (adjusted odds ratio [AOR], 1.11 [95% CI, 1.04-1.19]; P = .002) and during childhood (AOR, 1.09 [95% CI, 1.00-1.10]; P = .04) were associated with elevated odds for psychotic experiences. Pregnancy PM2.5 exposure was also associated with depression (AOR, 1.10 [95% CI, 1.02-1.18]; P = .01). Higher noise pollution exposure in childhood (AOR, 1.19 [95% CI, 1.03-1.38]; P = .02) and adolescence (AOR, 1.22 [95% CI, 1.02-1.45]; P = .03) was associated with elevated odds for anxiety. In this longitudinal cohort study, early-life air and noise pollution exposure were prospectively associated with 3 common mental health problems from adolescence to young adulthood. There was a degree of specificity in terms of pollutant-timing-outcome associations. Interventions to reduce air and noise pollution exposure (eg, clean air zones) could potentially improve population mental health. Replication using quasi-experimental designs is now needed to shed further light on the underlying causes of these associations.

Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations areassociated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.