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Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia.
Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43 years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression.
Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11 months) before the cognitive examination was associated with better cognitive performance (P = 0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P = 0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition.
Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia.
Due to the paucity of previous studies, we wanted to elucidate the pharmacoepidemiology of antipsychotics in schizophrenia in a general population sample, and the association between long-term antipsychotic use and outcomes.
The sample included 53 schizophrenia subjects from the Northern Finland Birth Cohort 1966 with at least ten years of follow-up (mean 18.6 years since illness onset). Data on lifetime medication and outcomes (remission, Clinical Global Impression [CGI], Social and Occupational Functioning Assessment Scale [SOFAS]) were collected from medical records, interviews, and national registers.
During the first two years 22 (42%), between two to five years 17 (32%), and between five to ten years 14 (26%) subjects had used antipsychotics less than half of the time. Drug-free periods became rarer during the follow-up. The mean lifetime daily dose of antipsychotics was 319 mg in chlorpromazine equivalents. A high lifetime average and cumulative dose and antipsychotic polypharmacy were associated with a poorer outcome in all measures, whereas having no drug-free periods was associated with a better SOFAS score and a low proportion of time on antipsychotics with a better CGI score.
In our population-based sample, the use of antipsychotics increased during the first five years of illness and was relatively stable after that. Our results suggest that both low dose and proportion of use, and having no drug-free periods, are associated with better outcomes, which concords with current treatment recommendations and algorithms. High long-term doses and polypharmacy may relate to poor outcomes.
In schizophrenia, brain morphometric changes may be associated with antipsychotic medication. Only limited data is available concerning individuals with schizophrenia without antipsychotic medication. We aimed to study the associations of: use versus no use of antipsychotic medication; length of continuous time without antipsychotic medication; cumulative dose of lifetime antipsychotic medication; and type of antipsychotic medication; with brain morphometry in schizophrenia after an average of 10 years of illness.
Data of 63 individuals with schizophrenia (mean duration of illness 10.4 years) from the Northern Finland Birth Cohort 1966 were gathered by interview and from hospital and outpatient records. Structural MRI data at age 34 years were acquired and grey matter volume maps with voxel-based morphometry were analyzed using FSL tools.
Of the individuals studied, 15 (24%) had taken no antipsychotic medication during the previous year. Individuals with antipsychotic medication had lower total grey matter (TGM) volume compared with non-medicated subjects, although this association was not statistically significant (Cohen's d = –0.51, P = 0.078). Time without antipsychotic medication associated with increased TGM (P = 0.028). Longer time without antipsychotic medication associated with increased regional volume in right precentral gyrus and right middle frontal gyrus. There were no associations between cumulative dose of lifetime antipsychotic medication or type of antipsychotic medication and brain morphometry.
Unlike some previous investigators, we found no association between cumulative dose of lifetime antipsychotic medication and brain morphological changes in this population-based sample. However, longer continuous time without antipsychotic medication preceding the MRI scan associated with increased gray matter volume.
Long duration of untreated psychosis (DUP) predicts poor short- and long-term outcome in schizophrenia. It may also be a marker of resilience and associate with lower doses or shorter periods of using antipsychotic medication which may or may not be correlated with the association between DUP and outcome.
To study the association between DUP and the use of antipsychotic medication in long-term follow-up.
To find out whether the delayed treatment in first-episode psychosis associates with using less antipsychotic medication during the course of illness
In the prospective Northern Finland 1966 Birth Cohort length of DUP and information on lifetime use of antipsychotic medication for 60 individuals with schizophrenia was assessed from medical records from the first episode until age 34 years. Association between length of DUP and cumulative dose-years of antipsychotics was analysed using linear regression analysis. Logarithmic transformations of DUP and dose years were used.
Mean DUP was 227 days (SD 359) and mean of cumulative dose years was 2.41 (SD 1.29). Symptoms measured using PANSS ranged from 30 to 122, mean 53 (SD 21). Duration of untreated psychosis did not associate with the use of antipsychotic medication (beta = −0.124, p = 0.343).
There was no evidence of an association between DUP and the use of antipsychotic medication. Although long DUP has long-term association with poor outcome, it does not have an association with the use of antipsychotic medication based on the population-based long-term follow-up.
The effects of long-term antipsychotic medication on cognition in schizophrenia are unclear (Husa A.P. et al., Schizophr. Res. 2014).
Understanding how long-term antipsychotic treatment affects cognition is crucial for the development of safe, evidence-based treatment of schizophrenia.
To analyse the association between cumulative lifetime antipsychotic dose and cognition in schizophrenia at age 43 years in a general population sample.
Sixty (33 males) schizophrenia spectrum subjects from the Northern Finland Birth Cohort 1966 were assessed at age 43 years by California Verbal Learning Test, Visual Object Learning Test, Abstraction Inhibition and Working Memory task, Verbal fluency, Visual series, Vocabulary, Digit Span and Matrix reasoning. Cumulative lifetime antipsychotic dose-years were collected from treatment records and interviews. A factor analysis based on the cognitive tests resulted in one cognitive factor. The association between this cognitive composite score and antipsychotic dose-years was analysed by linear regression.
Higher lifetime antipsychotic dose-years were statistically significantly associated with poorer cognitive composite score at age 43 years (B=-0.32, p>0.001), also when adjusted for gender, onset age, remission and number of hospital treatment days (B=-0.42, p=0.008).
To our knowledge, this is the first report of an association between cumulative lifetime antipsychotic dose and cognition in midlife in schizophrenia. Based on this data, the use of high antipsychotic doses may relate to poorer cognitive functioning in schizophrenia after twenty years of illness. These results do not support the view that antipsychotics prevent cognitive decline or promote cognitive recovery in schizophrenia.
Though neurocognitive dysfunctions are common in schizophrenia, the course and predictors of change of cognition remain uncertain.
To understand the longitudinal changes and their predictors in cognition, which is important for the etiological investigation of schizophrenia.
Aims. To analyse if premorbid school performance, age of illness onset and the severity of illness predicts change in cognition in schizophrenia in a general population sample.
The sample included cases with schizophrenia spectrum disorder from the Northern Finland 1966 Birth Cohort. Data on school marks at age 16 yearsand severity of symptoms and occupational functioning around first episode and after years of illness were gained from national registers, hospital notes and interviews. Verbal and visual memory and executive functioning were measured twice, at ages 34 and 43 years. The number of cases varied in analyses from 29 to 41, depending on the analysed cognitive test.
Association between lower school marks at age 16-years and decrease in executive functioning (p=0.032) and visual learning and memory (p=0.039) was found, even when adjusted by age of illness onset and cognitive functioning at age 34-years. Change of cognition was not predicted by severity of symptoms nor occupational functioning. Male gender associated to decrease of executive functioning (p=0.032) and earlier age of illness onset to decrease of visual learning and memory (p=0.045).
School performance at age 16 years associates to later longitudinal change of cognition. Based on our results, later cognitive functioning may reflect the evolution of schizophrenia illness.
To analyse associations between brain morphology and longitudinal and cross-sectional measures of outcomes in schizophrenia in a general population sample.
The sample was the Northern Finland 1966 Birth Cohort. In 1999–2001, structural brain MRI and measures of clinical and functional outcomes were analysed for 54 individuals with schizophrenia around the age of 34. Sex, total grey matter, duration of illness and the use of antipsychotic medication were used as covariates.
After controlling for multiple covariates, increased density of the left limbic area was associated with less hospitalisations and increased total white matter volume with being in remission. Higher density of left frontal grey matter was associated with not being on a disability pension and higher density of the left frontal lobe and left limbic area were related to better functioning. Higher density of the left limbic area was associated with better longitudinal course of illness.
This study, based on unselected general population data, long follow-up and an extensive database, confirms findings of previous studies, that morphological abnormalities in several brain structures are associated with outcome. The difference in brain morphology in patients with good and poor outcomes may reflect separable aetiologies and developmental trajectories in schizophrenia.
We analyzed longitudinal course of illness in schizophrenia until age 43 years, and its correlates to antipsychotic medication and cognition.
Northern Finland 1966 Birth Cohort Study has been followed serially since mid-pregnancy. Structural and functional MRI, cognitive, and clinical examinations were performed at ages 34 (73 schizophrenic psychoses, 104 controls) and 43 (63 schizophrenic psychoses, 192 controls); 40 cases and 75 controls participated in both surveys. Psychiatric outcomes have been ascertained through data linkage to a national case registers, hospital charts and clinical evaluations.
Prognosis of schizophrenia is heterogeneous: minority of individuals experience recovery, some achieve remission, but many are on disability pension, and excess mortality (especially suicides) is common. Long duration of untreated psychosis, early age of illness onset and presence of suicidal ideation associated with poorer long-term outcome. Both cases and non-psychotic controls show a small decline in verbal learning and memory, but the difference in decline is not significantly more pronounced in cases. Higher doses of antipsychotics at age 43-years associated to lower education and poorer clinical and functional outcomes, and high cumulative life-time use of antipsychotics associated to decrease of verbal learning and memory in 9-year follow-up.
Based on this naturalistic sample, midlife progression of schizophrenia may follow a variety of different trajectories. Poor clinical course is common but not necessary outcome. Compared to controls, more pronounced cognitive decline was not seen in schizophrenia cases. However, high doses of antipsychotics may relate to a decrease of verbal learning and memory.
The participation rates in epidemiologic studies have declined in recent decades. Missing data reduce sample size, statistical power, and scientific quality.
To study use of home interviews in recruiting individuals with a psychosis.
To evaluate effect of home-recruitment on non-response bias.
In the Northern Finland 1966 Birth Cohort, field surveys on psychosis were conducted in 1999-2001 and 2008-2010. In order to increase participation in the follow-up sample, cases were offered to be interviewed at home. We studied symptoms, illness severity, functioning, cognition, antipsychotics use, and grey matter (GM) volume between home-recruited and regular participants (RP), and non-participants (NP). Effect sizes (d) were calculated to compare the differences.
Altogether 18 (33%) out of the follow-up sample (n=54) were home-recruited, 27 did not participate. Home-recruited had more symptoms, lower functioning, cognition and GM volume, and they had used more antipsychotics compared to RP and NP in baseline. NP did not differ from RP. The same differences occurred when home-recruited were compared with RP in the follow-up study.
[Selected information from baseline study]
CVLT, total recall
Grey matter volume
Owing to the home-recruitment we were able to collect data that may be reasonably non-biased in terms of nonresponse bias, which will yield valid estimates in our future studies on change over time in brain and cognitive ability, prevalence and severity of psychotic illnesses, outcome, medication use, and other issues of interest.
Recently many studies have suggested more brain morphometric changes occurring in people with schizophrenia who use antipsychotic medication compared to those who do not.
We will study the brain morphology of subjects with schizophrenia spectrum disorder with and without antipsychotic medication.
Our aim was to compare the brain morphology of subjects with schizophrenia spectrum disorder with and without antipsychotic medication after in average ten years of illness, and analyse the association between cumulative dose of lifetime antipsychotic medication and brain morphology.
Data of 66 subjects with schizophrenia spectrum disorder (mean duration of illness 10.4 years) from the Northern Finland 1966 Birth Cohort were gathered by interview and from hospital records. Structural MRI data at age 34 years were acquired from all participants on a GE Signa system operating at 1.5T.
Of the subjects 16 (24%) had taken no antipsychotics during the previous year. We found no significant differences on total grey matter volumes (TGM) between subjects with and without antipsychotic medication. In the voxel-based analyses subjects with medication had lower volume in left parahippocampal gurys (p = 0.003), when adjusted for sex, onset age, TGM and remission status. There were no associations between lifetime antipsychotic dose and brain morphology.
We were able to study effects of antipsychotic medication in population-based sample. Brain morphology in medicated and non-medicated persons were similar and the cumulative lifetime medication had no effect on brain morphology, which suggests that possible medication effect in cross-sectional measures of brain morphology is small.
Long duration of untreated psychosis (DUP) has been associated to brain morphological changes in schizophrenia in cross sectional analyses. It is unclear DUP relates to brain volume change over time.
Our aim was to analyze the association between length of DUP and total brain volume change in schizophrenia in a general population based sample.
All members of the Northern Finland 1966 Birth Cohort (NFBC1966) known to have had psychotic illness were invited for a field study at the age 34-years (in average 10 year after onset of psychosis) and follow up nine years later at the age 43-years. DUP was assessed from medical records. The total brain volume scan interval change and the DUP information were available for 32 subjects with DSM III R schizophrenia. We analysed the correlation between length of DUP and the mean annual whole brain reduction, adjusted for age of illness onset and sex.
The mean annual whole brain volume reduction was 0.66%. The reduction was 0.76% among those with shortest DUP, 0.58% among those with median DUP, and 0.63% among those with longest DUP. There was no statistically significant correlation between DUP and annual brain volume change when adjusted for onset age and/or sex.
We did not find an association between long DUP and brain volume decrease in schizophrenia in 9 years follow up. Although long DUP has been associated with differences in brain volume in cross sectional analyses, the significance of DUP on brain morphology in long term is unclear.
Cognitive deficits, such as verbal memory dysfunction, are a core feature of schizophrenia. Yet the longitudinal course and associations of cognitive deficits with antipsychotic medication remain unclear.
Our aim was to analyze how lifetime antipsychotic dosage associates with the change of verbal learning and memory in individuals with schizophrenia during a 9-year follow-up.
Forty-two subjects with schizophrenic psychoses (22 males) from the Northern Finland 1966 Birth Cohort went through diagnostic interviews and cognitive assessment including California Verbal Learning Test (CVLT) at the ages of 34 and 43 years. Data of the subjects’ lifetime antipsychotic doses in chlorpromazine equivalents were collected from patient history records, interviews and national registers. The association between verbal learning and memory (immediate free recall of trials 1-5 and free recall after long delay) and dose-years of antipsychotics was analyzed by logistic regression model.
Higher dose-years of any and typical antipsychotics, but not atypical antipsychotics, associated statistically significantly to worse verbal learning and memory in cross-sectional analyses at age 34 years, even when onset age, sex, and severity of symptoms were controlled for. However, there was no statistically significant association between lifetime antipsychotic use and verbal learning and memory change between ages 34 and 43 years.
High lifetime antipsychotic dose did not associate to decrease in verbal learning and memory in schizophrenia in 9 years of follow-up. To our knowledge, this is a first report on association between cumulative lifetime antipsychotic use and change in cognition in a long-term naturalistic follow-up.
Patients with schizophrenia generally perform worse than control subjects on all cognitive domains, and particularly in memory functions. It is still unclear, how cognition changes during years of illness in schizophrenia.
Our aim was to analyze the change in verbal learning and memory functions in subjects with schizophrenia and healthy controls during a 9-year follow-up.
The sample was the general population based Northern Finland 1966 Birth Cohort. In 1999-2001 and in 2008-2010 field studies were performed, including repeated measures of clinical status and the California Verbal Learning Test (CVLT). CVLT was used for the estimation of the course of a possible change of verbal learning and memory during the follow-up. The sample included 41 individuals with schizophrenic psychoses and 74 non-psychotic controls.
Both cases and controls had statistically significant decline in measures of CVLT. However, the change in verbal learning and memory in the 9 -year follow-up was not statistically significantly different between cases and controls. Among cases, age of illness onset and sex had no statistically significant effect on change of verbal learning and memory.
According to our unselected, population based sample with long follow up, the impairments during the life span in verbal learning and memory in schizophrenia was not different compared to controls. These results imply that schizophrenia is not a progressing degenerative illness.
To estimate the prevalence of non-medicated subjects having schizophrenia spectrum disorder and to study how they differ from medicated subjects in terms of sociodemographic and illness-related variables. We also aim to find the predictors for successful antipsychotic withdrawal.
Data of 70 subjects with schizophrenic psychoses (mean duration of illness 10.4 years) from the Northern Finland 1966 Birth Cohort were gathered by interview at the age of 34 and from hospital records. The stability of remission was assessed by comparing hospitalization rates between non-medicated and medicated subjects over an 8.7-year additional follow-up period.
Twenty-four (34%) subjects were currently not receiving medication. They were more often males, less often on a disability pension, more often in remission, and had better clinical outcomes. Relapses during the follow-up were equally frequent between non-medicated and medicated subjects (47% vs. 56%). Not having been hospitalised during previous 5 years before the interview predicted long-term successful antipsychotic withdrawal without relapse.
Despite a lack of precise predictors, there might be subgroup of schizophrenia spectrum subjects who do not need permanent antipsychotic medication, and a fewer previous psychiatric treatments may indicate such a subgroup.
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