Pathomechanisms and Signatures in the Longitudinal Course of Psychosis



026_ Influence of Early Life Stress on cognition, psychopathology, level of Functioning in patients with schizophrenia

Research Question and Aims

Research object: The childhood trauma screener (Bernstein et al., 2003) is an instrument to assess early life stressors (ELS) on a fivepoint scale. In patients with schizophrenia (SZ) and in control subjects (C) it shall be analyzed, if patients and control subjects with ELS show deficits in neuropsychological test results, psychopathology (PANSS), severity of the illness (CGI) and global functioning (GAF). State of the research: Environmental risk factors such as childhood trauma or bullying have been shown to increase the risk to develop affective and non-affective schizophrenia (Aldinger & Schulze 2017; Schmitt, Malchow, Hasan, & Falkai, 2014), and are linked to onset of psychosis and worse social functioning (Yung et al., 2015). The most frequent exposure to early stress in form of childhood trauma is emotional neglect, but also physical abuse and physical neglect are more frequent in schizophrenia patients (Bonoldi et al., 2013; Larsson et al., 2013). Childhood abuse and neglect are known to have a negative influence on cognition in patients with schizophrenia (Shannon et al., 2011). Beside impaired social cognition (Kilian et al., 2017), subdomains of childhood trauma such as physical and sexual abuse and physical neglect have been reported to be associated with reduced scores on working memory, executive function, verbal memory and attention (Aas et al., 2012; Li et al., 2017).

Analytic Plan

Hypothesis: It is hypothesized that subjects with ELS are impaired in neuropsychology and psychopathology and that schizophrenia patients and controls with ELS are equally affected. Further it is hypothesized, that outcome measures improve more slowly in subjects with ELS than in subjects without ELS (No-ELS).

Population stratification: As initial analysis it will be examined if age, gender, education, and treatment (inpatients vs. outpatients) affect the outcome measures. If necessary, a subsample matched for these intervening variables will be created. However, the primary analytical strategy is to take into account the influence of these intervening variables in analyses of covariance. Outcome measures: Neuropsychology: TMT-A and TMT-B time, Digit span test, Digit Symbol test, VLMT. Psychopathology (PANSS total score), severity of the disease (CGI) (not available for controls), global assessment of functioning (GAF).

Quality control methods: All variables will be examined for impossible values, for outliers and extreme values, which will be excluded from the analysis, if they are based with a high probability on incorrect data.

Analytic methods: Primary analyses will include data at the time, when the ELS data were collected (V3). When the assumptions are fulfilled, parametric methods (analysis of covariance, ANCOVA) will be performed. If required analyses will appropriately be adjusted for age, gender, education, and treatment. Nonparametric methods (Mann-Whitney U tests) will be applied, if for an outcome variable there are strong deviations from normality assumption and if no covariates have to be included. It will be analyzed, if ELS data is correlated with abuse of alcohol or illicit drugs, disease duration, number of illness episodes, course of the disease (opcrit atV4), intelligence (MWT-B), medication (number of used antipsychotics), depressive symptoms (BDI-II, IDS-C) and family history for psychiatric illness. The results on neuropsychology tests and psychopathology will be adjusted for multiple testing, applying the Benjamini-Hochberg (Benjamini & Hochberg, 1995) procedure.
For longitudinal analysis (V1 until V4), repeated measures ANCOVA will be performed, or if this is not possible nonparametric methods (Wilcoxon tests) will be used. Only if for an outcome variable significant differences between ELS and No-ELS are found, subsequent analyses for each of the five ELS items will be performed.

Statistical power: Assuming ANCOVA as analysis method, a medium effect size (f = 0.25), α = 0.005 (corrected for multiple testing), a power of 1-ß = 0.8, 4 groups (SZ with and without ELS, controls with and without ELS), and 1 covariate a total sample of 218 will be needed (Faul, Erdfelder, Lang, & Buchner, 2007). Therefore, the available sample size will be sufficient to find even smaller effects. Post hoc power analyses will be performed.

Resources needed

ELS variables:
ELS total: v3_cts_els_dic
Item 1: feeling of not to be loved v3_cts_1
Item 2: physical violence v3_cts_2
Item 3: feeling of being hated v3_cts_3
Item 2: sexual abuse v3_cts_4
Item 2: no one cared v3_cts_5

Identification code v1_id
Clinical/conrol status v1_stat
Gender: v1_sex Age (at first interview, years): v1_ageBL
Marital status: v1_marital_stat
Partnership status: v1_partner
Children: v1_no_bio_chld
Siblings: V1_brothers
Living alone?: v1_liv_alone
School education: v1_school
Professional education: v1_prof_dgr
Currently paid employment?: v1_curr_paid_empl
Months of work absence (last 5 years) v1_wrk_abs_pst_5_yrs
Country of birth v1_cntr_brth

Visit V1
Motivation for neuropsychological tests: v1_nrpsy_mtv
TMT-A (time): v1_nrpsy_tmt_A_rt
TMT-A (errors): v1_nrpsy_tmt_A_err
TMT-B (time): v1_nrpsy_tmt_B_rt
TMT-B (errors): v1_nrpsy_tmt_B_err
Digit Span Test (forward): v1_nrpsy_dgt_sp_frw
Digit Span Test (backward): v1_nrpsy_dgt_sp_bck
Digit Symbol Test: v1_nrpsy_dg_sym
Intelligence: v1_nrpsy_mwtb (see clinical variables, intervening variables)

Visit V2
Motivation for neuropsychology: v2_nrpsy_mtv
VLMT correct: v2_nrpsy_vlmt_corr
VLMT Loss of recalled words (V5 - V6 ): v2_nrpsy_vlmt_lss_d
VLMT Loss of recalled words (V5 - V7 ): v2_nrpsy_vlmt_lss_t
VLMT Recognition: v2_nrpsy_vlmt_rec
TMT-A (time): v2_nrpsy_tmt_A_rt
TMT-A (errors): v2_nrpsy_tmt_A_err
TMT-B (time): v2_nrpsy_tmt_B_rt
TMT-B (errors): v2_nrpsy_tmt_B_err
Digit Span Test (forward): v2_nrpsy_dgt_sp_frw
Digit Span Test (backward): v2_nrpsy_dgt_sp_bck
Digit Symbol Test: v2_nrpsy_dg_sym

Visit V3
Motivation for neuropsychology: v3_nrpsy_mtv
VLMT correct: v3_nrpsy_vlmt_corr
VLMT Loss of recalled words (V5 - V6 ): v3_nrpsy_vlmt_lss_d
VLMT Loss of recalled words (V5 - V7 ): v3_nrpsy_vlmt_lss_t
VLMT Recognition: v3_nrpsy_vlmt_rec
TMT-A (time): v3_nrpsy_tmt_A_rt
TMT-A (errors): v3_nrpsy_tmt_A_err
TMT-B (time): v3_nrpsy_tmt_B_rt
TMT-B (errors): v3_nrpsy_tmt_B_err
Digit Span Test (forward): v3_nrpsy_dgt_sp_frw
Digit Span Test (backward): v3_nrpsy_dgt_sp_bck
Digit Symbol Test: v3_nrpsy_dg_sym

Visit V4
Motivation for neuropsychology: v4_nrpsy_mtv
VLMT correct: v4_nrpsy_vlmt_corr
VLMT Loss of recalled words (V5 - V6 ): v4_nrpsy_vlmt_lss_d
VLMT Loss of recalled words (V5 - V7 ): v4_nrpsy_vlmt_lss_t
Recognition: v4_nrpsy_vlmt_rec
TMT-A (time): v4_nrpsy_tmt_A_rt
TMT-A (errors): v4_nrpsy_tmt_A_err
TMT-B (time): v4_nrpsy_tmt_B_rt
TMT-B (errors): v4_nrpsy_tmt_B_err
Digit Span Test (forward): v4_nrpsy_dgt_sp_frw
Digit Span Test (backward): v4_nrpsy_dgt_sp_bck
Digit Symbol Test: v4_nrpsy_dg_sym

Psychopathology and functioning:
Visit V1
PANSS positive v1_panss_sum_pos
PANSS negative v1_panss_sum_neg
PANSS general v1_panss_sum_gen
PANSS total v1_panss_sum_tot
Illness severity (CGI) V1_CGI_S
Functioning V1_GAF

Visit V2
PANSS positive v2_panss_sum_pos
PANSS negative v2_panss_sum_neg
PANSS general v2_panss_sum_gen
PANSS total v2_panss_sum_tot
Illness severity (CGI) V2_CGI_S
Functioning V2_GAF

Visit V3
PANSS positive v3_panss_sum_pos
PANSS negative v3_panss_sum_neg
PANSS general v3_panss_sum_gen
PANSS total v3_panss_sum_tot
Illness severity (CGI) V3_CGI_S
Functioning V3_GAF

Visit V4
PANSS positive v4_panss_sum_pos
PANSS negative v4_panss_sum_neg
PANSS general v4_panss_sum_gen
PANSS total v4_panss_sum_tot
Illness severity (CGI) V4_CGI_S
Functioning V4_GAF
Assessment of disease course v4_opcrit

Clinical variables, intervening variables:
Visit V1
Diagnosis v1_scid_dsm_dx
Major Depression Episodes? v1_scid_ever_MDE
Treatment (inpatients vs. outpatients): v1_cur_psy_trm
Disease duration (years): v1_dur_illness
Number hospitalizations (as daypatient or inpatient): v1_tms_daypat_outpat_trm
Family history of psychiatric illness: v1_fam_hist
Alcohol: alcohol consume last 12 months: v1_alc_pst12_mths
strong alcohol consume last 6 months: v1_alc_5orm
alcohol dependence lifetime: v1_lftm_alc_dep
Ever used illicit drugs?: v1_evr_ill_drg
Intelligence (MWT-B): v1_nrpsy_mwtb
Depressive symptoms: v1_bdi2_sum
Suicide thoughts: v1_scid_evr_suic_ide

Medication data (Antipsychotika (ja/nein), Anzahl Med.)

Visit V2
Illness episodes since last visits: v2_ill_ep_snc_lst
Number Illness episodes: v2_no_ep
Alcohol: alcohol consume last 6 months: v2_alc_pst6_mths
strong alcohol consume last 6 months: v2_alc_5orm
Illicit drugs last 6 months?: v2_pst6_ill_drg
Depressive symptoms: v2_bdi2_sum

Medikation data (Antipsychotika (ja/nein), Anzahl Med.)

Visit V3
Illness episodes since last visits: v3_ill_ep_snc_lst
Number Illness episodes: v3_no_ep
Alcohol: alcohol consume last 6 months: v3_alc_pst6_mths
strong alcohol consume last 6 months: v3_alc_5orm
Illicit drugs last 6 months?: v3_pst6_ill_drg
Depressive symptoms: v3_bdi2_sum

Medikation data (Antipsychotika (ja/nein), Anzahl Med.)

Visit V4
Illness episodes since last visits: v4_ill_ep_snc_lst
Number Illness espisodes: v4_no_ep
Alcohol: alcohol consume last 6 months: v4_alc_pst6_mths
strong alcohol consume last 6 months: v4_alc_5orm
Illicit drugs last 6 months?: v4_pst6_ill_drg
Depressive symptoms: v4_bdi2_sum

Medikation data (Antipsychotika (ja/nein), Anzahl Med.)