Jani Moilanen

Longitudinal changes in total brain volume in schizophrenia: relation to symptom severity, cognition and antipsychotic medication.

Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999–2001 at the age of 33–35 years. A follow-up was conducted 9 years later during 2008–2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions.

Lifetime use of antipsychotic medication and its relation to change of verbal learning and memory in midlife schizophrenia — An observational 9-year follow-up study

BACKGROUND The association between the course of cognition and long-term antipsychotic medication in schizophrenia remains unclear. We analysed the association between cumulative lifetime antipsychotic medication dose and change of verbal learning and memory during a 9-year follow-up. METHOD Forty schizophrenia subjects and 73 controls from the Northern Finland Birth Cohort 1966 were assessed by California Verbal Learning Test (CVLT) at the ages of 34 and 43 years. Data on the lifetime antipsychotic doses in chlorpromazine equivalents were collected. The association between antipsychotic dose-years and baseline performance and change in CVLT was analysed, controlling for baseline performance, gender, age of onset and severity of illness. RESULTS Higher antipsychotic dose-years by baseline were significantly associated with poorer baseline performance in several dimensions of verbal learning and memory, and with a larger decrease in short-delay free recall during the follow-up (p=0.031). Higher antipsychotic dose-years during the follow-up were associated with a larger decrease of immediate free recall of trials 1-5 during the follow-up (p=0.039). Compared to controls, decline was greater in some CVLT variables among those using high-doses, but not among those using low-doses. CONCLUSION This is the first report of an association between cumulative lifetime antipsychotic use and change in cognition in a long-term naturalistic follow-up. The use of high doses of antipsychotics may be associated with a decrease in verbal learning and memory in schizophrenia years after illness onset. The results do not support the view that antipsychotics in general prevent cognitive decline or promote cognitive recovery in schizophrenia.

Longitudinal regional brain volume loss in schizophrenia: Relationship to antipsychotic medication and change in social function

Background Progressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators. Method Participants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age = 34.7, SD = 0.77) and at follow-up (mean age = 43.4, SD = 0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA. Results Schizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction. Conclusion Our findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions.

Lifetime antipsychotic medication and cognitive performance in schizophrenia at age 43 years in a general population birth cohort.

This naturalistic study analysed the association between cumulative lifetime antipsychotic dose and cognition in schizophrenia after an average of 16.5 years of illness. Sixty participants with schizophrenia and 191 controls from the Northern Finland Birth Cohort 1966 were assessed at age 43 years with a neurocognitive test battery. Cumulative lifetime antipsychotic dose-years were collected from medical records and interviews. The association between antipsychotic dose-years and a cognitive composite score based on principal component analysis was analysed using linear regression. Higher lifetime antipsychotic dose-years were significantly associated with poorer cognitive composite score, when adjusted for gender, onset age and lifetime hospital treatment days. The effects of typical and atypical antipsychotics did not differ. This is the first report of an association between cumulative lifetime antipsychotic dose and global cognition in midlife schizophrenia. Based on these data, higher lifetime antipsychotic dose-years may be associated with poorer cognitive performance at age 43 years. Potential biases related to the naturalistic design may partly explain the results; nonetheless, it is possible that large antipsychotic doses harm cognition in schizophrenia in the long-term.

Use of psychiatric medications in schizophrenia and other psychoses in a general population sample

The information on the use of psychiatric medications in general population-based samples is limited. Our aim was to analyse the use of psychiatric medications and factors associated with antipsychotic use in psychoses in a general population sample. Fifty-five persons with schizophrenia, 21 with bipolar psychosis or psychotic depression and 20 with other psychoses from the Northern Finland Birth Cohort 1966 were examined at about 43 years of age. The frequency of use and dosage of psychiatric medication and the factors associated with the use of antipsychotics were analysed. Antipsychotics were used by 85% of schizophrenia, 65% of bipolar psychosis or psychotic depression and 62% of other psychoses cases; antidepressants were used by 22%, 60% and 33%; and benzodiazepines by 42%, 35% and 10%, respectively. In all the diagnostic groups, higher symptom scores and a higher number of hospital days were associated with the use of antipsychotics. In schizophrenia and other psychoses, poorer social and occupational functioning, and in other psychoses, female gender and lower education were also associated with the use of antipsychotics. Our results may partly indicate that, especially in schizophrenia, the effectiveness of antipsychotics is not as good as expected.

Long-term antipsychotic and benzodiazepine use and brain volume changes in schizophrenia: The Northern Finland Birth Cohort 1966 study

High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning.

Lifetime use of psychiatric medications and cognition at 43 years of age in schizophrenia in the Northern Finland Birth Cohort 1966

BACKGROUND 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. METHODS Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43years 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. RESULTS Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11months) 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. CONCLUSIONS 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.

Under-utilized opportunities to optimize medication management in long-term treatment of schizophrenia

Millions of people use antipsychotic medications and thousands of clinicians prescribe and monitor this treatment every day worldwide. In their review, Correll et al highlight key issues regarding the long-term use of these medications. Herein we further discuss such issues, based on additional literature and data from Finnish cohort studies. Three cornerstones in the long-term medication of schizophrenia are evidencebased use of antipsychotics, adjuvant psychosocial therapies, and optimal medication management. Correll et al review key findings and problems with the first and second of these cornerstones. Could good medication management alleviate these problems? Medication management is defined as a process aimed to facilitate safe and effective use of medications and optimize therapeutic outcomes. Multiple models of medication management have been put forward, but no systematic reviews, meta-analyses or universal treatment recommendations are available. Incomplete evidence on the content and cost-effectiveness of optimal antipsychotic medication management must be balanced with the development of organizationspecific practices. Proper approaches to medication management include shared decision making in prescription, follow-up, and monitoring at regular intervals. In addition, careful documentation of response, continuity, and coordination of care should be ensured by a well-trained multidisciplinary team. However, in clinical practice, medication management is often suboptimal. Schizophrenia patients with impaired cognition or motivation and/or poor financial resources have an elevated risk of inadequate medication management. Important principles include avoiding maximal doses and polypharmacy, in favor of using the lowest possible effective and tolerated dose, choosing an antipsychotic associated with minimal side effects, and using adjuvant psychosocial interventions. For instance, maximal psychosocial and medication management interventions reduced the mean dose of antipsychotics from 370 to 160 mg/day as chlorpromazine equivalents in a Finnish therapeutic community ward of patients with acute psychosis. However, currently used doses may sometimes be too high, as a reflection of insufficient or missing psychosocial therapies or poor medication management. Current clinical practice guidelines are non-specific with respect to optimal doses, dose tapering, low-dose maintenance and discontinuation of antipsychotics. Guidelines do not specify how to go about tapering (i.e., at what point in the clinical course of illness, over what time period). This uncertainty may induce clinicians to set the bar high in dose reduction or withdrawal owing to potential risks. In practice, changes in antipsychotic dosing are done by testing and monitoring clinical response in the individual patient. This testing presupposes good medication management. A vital long-term aim in medication management is to minimize unwanted drug effects such as tardive dyskinesia, weight gain or metabolic disturbances. Adverse effects attributable to chronic antipsychotic exposure are often cumulative over a period of years. A metaanalysis found associations between long-term antipsychotic use and brain volume changes. Antipsychotics may also impact on brain plasticity and cognitive functioning. Brain effects appear to be dose-dependent: high cumulative doses are related to brain alterations and cognitive decline. Paying attention to side effects, and adjusting and trying to find the lowest effective and tolerated dose could also decrease the dramatically high prevalence of medication nonadherence in schizophrenia. As stressed by Correll et al, there are major methodological challenges when studying long-term antipsychotic use. Scientific evidence on dose reduction or medication discontinuation is primarily based on observational studies, which are subject to potential biases. Randomized controlled trials (RCTs) can help determine only the short-term efficacy and adverse effects. Such trials tend to be reductionistic when analyzing the complex interactions between brain, environment, drug effects and care. RCTs tend not to detect different subgroup effect sizes and longterm advantages and harms. Non-adherence and attrition are also alarming problems in medication studies. Effective medication management may reduce them. In the Northern Finland Birth Cohort 1966 Study, we initially had a low participation rate of patients during the 9-year follow-up (44%). With maximal management efforts, including home visits, the participation rate increased in subsequent follow-ups (67%). There are no major breakthroughs in the efficacy of antipsychotic treatment in sight. Current antipsychotics diminish illness expression, but do not restore lost complex brain functions. Many patients (and clinicians) do not utilize these medications optimally, even though their efficacy is quite high. Improving medication management and thus the risk-benefit ratio of antipsychotics is a realistic goal in the near future. In summary, current care guidelines and practice standards advise us on how to use antipsychotics, most definitively at the group level and during the first years of illness. Long-term use and medication management skills and services are inadequately studied. It is important to learn what not to do when aiming at long-term improvement in medication management. Do not leave the patient alone with the medication. Do not forget the intellectual power of and need for psychoeducation and social support to patients and relatives. Do not remain silent or uninformed on patients’ drug attitudes, treatment adherence, and negative experiences. Do not use only your brain, but also your heart and empathy.

T78. LONG-TERM PROGNOSIS OF SCHIZOPHRENIA - RESULTS FROM THE NORTHERN FINLAND BIRTH COHORT 1966

Abstract Background The aim of this study was to explore the prognosis and predictors of outcomes in schizophrenia in a birth cohort sample followed since mid-pregnancy until the age of 45 years. Methods The sample included subjects with schizophrenia (n=29–161, depending on the analyzed topic) from the Northern Finland Birth Cohort 1966. Outcomes and their predictors were analyzed by utilizing national registers, questionnaires and personal examinations made on several time points (e.g. during pregnancy, at age 1 year, 34- and 43- years). Functioning, amount of psychiatric symptoms, utilization of treatments, physical illnesses and mortality, and cognition were used as measures of outcomes. Several plausible factors associating to outcomes were studied, e.g. gender, family history of psychosis, development and childhood related factors, school performance, and illness related factors around the onset of psychosis, brain morphology and cognitive functioning, and lifetime antipsychotic medication. Results Around the age of 34-years recovery was possible though quite uncommon (3.4%), some persons achieved symptomatic remission (21%), and many were on disability pension (54%). Around the age of 43–45 years only 11.2% were employed, and 19% were in remission. Earlier age of illness onset, longer duration of untreated psychosis, suicidal ideation and poorer functioning around illness onset, brain morphological changes and poorer cognition, and higher lifetime doses of antipsychotics associated to poor outcomes. Cognition did not markedly decline from 34 to 43 years of age, but poorer premorbid school performance and higher lifetime doses of antipsychotics predicted more decline of cognition. For some cases, the cumulative amount of used antipsychotics was extensive. Somatic comorbidities were common, and mortality high. Discussion Based on this naturalistic sample, progression of schizophrenia may follow a variety of different trajectories. Poor clinical course is common but not necessary outcome. Our results indicate heterogeneous and still relatively unsatisfactory prognosis of schizophrenia in this sample. Several predictors of outcomes have been found, and especially factors related to illness onset and high lifetime cumulative dose of antipsychotics are of interest. Birth cohort setting offers unique possibility to study long-term prognosis of schizophrenia.

S230. LONG-TERM ANTIPSYCHOTIC MEDICATION IN SCHIZOPHRENIA: BENEFITS, RISKS AND FOLLOW-UP: DATA FROM FINNISH COHORT STUDIES AND SYSTEMATIC REVIEW

Abstract Background Millions of people use antipsychotic medications. Thousands of clinicians (often non-psychiatrists) prescribe and monitor them every day. Existing research reports mostly favorable risk-benefit ratio during the first years of schizophrenia, but their risk-benefit ratio and maintenance efficacy in long-term is not clear. Our aim was to: 1. analyze long-term antipsychotic use and its determinants in Finnish cohort samples, and 2. review the studies on benefits, risks, and follow-up and monitoring practices of long-term antipsychotic treatments. Methods 1. We used the data of population-based Northern Finland Birth Cohort 1966 (NFBC1966), and also Finnish therapeutic community data. 2. We performed a systematic literature search on long-term treatment effects, risks and monitoring of antipsychotic medication in schizophrenia. Results 1. In NFBC1966 in midlife, higher lifetime doses of antipsychotics were associated with alterations in brain morphometry, poorer neurocognition, and poorer clinical outcomes. Clinical follow-up was inadequate even in half of the schizophrenia cases. In therapeutic community cohort, maximal development of psychosocial care reduced the mean dose of antipsychotics in acute psychosis ward from 370 mg/day as chlorpromazine equivalents into 160 mg/day. 2. In the literature review, three main cornerstones in the high quality longitudinal use of antipsychotic medication were: a) high, evidence-based pharmacological quality, b) optimal adjuvant psychosocial therapies, c) sophisticated long-term prescription, monitoring and follow-up practices to minimize nonadherence and psychiatric and somatic failures. In sum, antipsychotics are effective for acute and mid-term psychosis in prevention of relapses and excess mortality. Long term antipsychotic use especially in high doses may include major iatrogenic harms, as also poorly monitored withholding or discontinuing. When aiming for an optimal benefit-risk ratio and for balancing symptomatic, functional and somatic outcomes, the goal is to aim for lower ranges of effective dosing, as well as choosing an appropriate antipsychotic agent that causes minimal side effects, and to combine adjuvant psychosocial interventions in the treatment. The often recommended personalized smallest effective dose is not so simple but still a realistic strategy in current relapse prevention practices, where doses often are too large for safety reasons. Discussion Cohort-based register studies are useful in examining long-term medication effects although they contain a risk of residual confounding due to their observational design. However, randomized controlled trials in long, over 3–7 years of follow-up, are unrealistic. The systematic literature review demonstrates major open or conflicting questions in risk-benefit ratio related to long-term outcomes. Non-adherence and attrition are key problems in sustained antipsychotic medication. Standardized prescription and monitoring practices (not so much studied) might improve medication adherence and also outcomes. Current clinical guidelines advise us based on studies from first years of schizophrenia. There are only few and weak patient-level predictors of successful tapering and discontinuation of antipsychotic medication. In the future, clinical follow-up of medication can be improved by structured follow-up and planned continuity. Life span view of antipsychotic medication stresses careful documentation of doses, responses and harms, longitudinal planning and realization of medication as part of the whole treatment program, as well as individualized and tailored selection, dosing (dose as low as possible or minimal effective dose) and follow-up by a well-trained team.