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Cognitive function, depression, and anxiety in patients undergoing radical prostatectomy with and without adjuvant treatment

Cognitive function, depression, and anxiety in patients undergoing radical prostatectomy with and... Journal name: Neuropsychiatric Disease and Treatment Article Designation: Original Research Year: 2019 Volume: 15 Running head verso: Jarzemski et al Neuropsychiatric Disease and Treatment Dovepress Running head recto: Jarzemski et al open access to scientific and medical research DOI: 200501 Open Access Full Text Article O rig i N al r esearch cognitive function, depression, and anxiety in patients undergoing radical prostatectomy with and without adjuvant treatment This article was published in the following Dove Medical Press journal: Neuropsychiatric Disease and Treatment Piotr Jarzemski Background: Prostate cancer (PC) is one of the most common malignant tumors in developed countries. Both PC and treatment for PC have an adverse impact on physical and mental well- Bartosz Brzoszczyk being, and are associated with decreased quality of life. The aim of the present study was to Alicja Popiołek examine the relationship between neuropsychological symptoms and clinical course in PC agnieszka patients undergoing radical prostatectomy with or without adjunct therapy. Stachowicz-Karpińska Methods: The cohort comprised 100 patients aged 50–77 years who underwent radical, Szymon Gołota laparoscopic prostatectomy for PC. Twenty-three patients with a more advanced clinical Maciej Bieliński stage also received adjuvant therapy (radiotherapy and hormonotherapy). Clinical evaluation alina Borkowska included self-report assessment, physical examination, and biochemical tests (testosterone and Department of laparoscopic, prostate-specific antigen). In addition, the presence and intensity of sexual dysfunction, urinary general, and Oncological Urology, dysfunction, anxiety-depressive symptoms, and cognitive dysfunction were assessed. Jan Biziel University hospital No 2, Bydgoszcz, Poland; Department of Results: The group of patients undergoing complex therapy was characterized by a significantly clinical Neuropsychology, Nicolaus worse result of deferred memory ( p=0.04). A significant correlation was found between post- Copernicus University in Toruń, surgery erectile function and scores for the visual working memory test (correct answers; collegium Medicum, Bydgoszcz, Poland VWMT-C; p=0.006) and Hospital Anxiety and Depression Scale depression ( p=0.045) and anxiety scores ( p=0.02). A trend toward significance was also observed for simple reaction time (correct answers; p=0.09). A significant correlation was found between results for the delayed verbal memory test and all physical symptoms (International Consultation on Incon- tinence Questionnaire-total, p=0.02; International Index of Erectile Function-5, p=0.006). Similarly, a significant correlation was found between the VWMT-C and score for sexual dysfunction ( p=0.003). Conclusion: Patients undergoing both surgical and adjunct therapy for PC are at risk for psychological burden and cognitive disorders. In the present cohort, physical complications of therapy were associated with depression, anxiety, and delayed memory dysfunction. Further- more, this study has proven that fewer complications after surgery are associated with better psychological and cognitive functioning. Appropriate neuropsychological and psychiatric care can improve compliance and quality of life among patients after prostatectomy. Keywords: prostate cancer, cognition, anxiety, depression, sexual dysfunction Introduction Correspondence: Maciej Bieliński Prostate cancer (PC) is one of the most common malignancies in developed countries. Department of clinical Neuropsychology, According to the American Cancer Society, among men in the US, PC is the most Nicolaus Copernicus University in Toruń, collegium Medicum, ul. Marii curie- frequently diagnosed malignant tumor and the second leading cause of cancer death Skłodowskiej 9, 85-094 Bydgoszcz, Poland (after lung cancer). Both PC and treatment for PC have a negative impact on physical Tel/fax +4 852 585 3703 2–7 email bielinskim@gmail.com and mental well-being, and are associated with decreased quality of life. PC is often submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 819–829 Dovepress © 2019 Jarzemski et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/NDT.s200501 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Jarzemski et al Dovepress diagnosed after presentation with disease-related physical urological outpatient department of the Jan Biziel University symptoms, and is frequently associated with anxiety con- Hospital No 2 in Bydgoszcz, Poland. The median age of 8–10 cerning treatment and its possible consequences. Primary the participants was 66 years (range: 50–77 years). Patients therapy for PC remains surgical radical prostatectomy. Over were evaluated once postoperatively, after an average of recent decades, numerous studies of PC have demonstrated 27 months (minimum after 3 and a maximum of 102). A a significant association between treatment method and the medical history was obtained and, if indicated, tests were 11–13 incidence of complications. All forms of surgical treat- performed to identify comorbid common diseases that have ment are associated with periprocedural and deferred com- an impact on cognitive function (diabetes, hypertension, plications, which impact both the physical and psychological previous myocardial infarction, and stroke). Patients with 2,13 aspects of quality of life. either a psychiatric disorder or addiction to illicit drugs or The most commonly reported postoperative physical symp- alcohol were excluded, as categorized by the Diagnostic 11,14 toms are sexual dysfunction and difficulties with micturition. and Statistical Manual of Mental Disorders, 4th edition, as The most common postoperative psychological symptoms were those with any neurological abnormality. The study 15–17 18,19 15,16,20 are anxiety, chronic fatigue, and depression. was approved by the Bioethical Commission of the Nicolaus Research has demonstrated an association between specific Copernicus University, Collegium Medicum in Bydgoszcz psychological symptoms and the prevalence and severity (Approval No 476/2017). All participants provided written of sexual and urinary outcomes in the PC population. informed consent prior to inclusion. All study procedures The most common forms of deterioration in sexual func- were performed in accordance with the principles of the tion in PC patients are erectile dysfunction (ED), difficulties Declaration of Helsinki. A control group, including 112 men in experiencing orgasm, shortening and/or deformation of (aged 48–76 years and matched to age, p=0.44), with no sig- 24,25 26 20 the penis, fertility disorders, and reduced sex drive. nificant somatic and mental diseases and in a stable clinical These symptoms are associated with a reduced sense of mas- condition for at least 6 months, was selected as a reference 27–30 culinity and physical attractiveness. Research shows that for the results of Neurotest. PC patients with treatment-related ED often blame themselves clinical Pc staging and biochemical for their postoperative sexual and relationship difficulties, and for their inability to meet the sexual needs of their measures partners. This is also the case for disorders of self-image Prior to surgery, clinical PC stage was assessed via mea- and self-confidence, which may also interfere with personal surement of prostate-specific antigen (PSA) and magnetic 29,32 relationships, in particular relationships with their partners. resonance imaging of the prostate. At follow-up, besides Research in PC patients has also demonstrated a signifi - complementary treatment, first (6 weeks post-surgery) and cant deterioration in cognitive function. Several studies have the actual PSA results were analyzed. In the adjunct therapy demonstrated that cognitive dysfunction in this population is subgroup, biochemical failure was defined as a 6-week PSA associated with hormonal disorders, including those arising as level of .0.2 ng/mL. Free testosterone was measured at 33–35 a result of hormonal therapy. In older adults from the non- 6-week postoperative follow-up using an electrochemilu- PC population, better scores for cognitive functioning have minescence immumoassay technique. All testosterone blood been associated with sexual satisfaction and the frequency of samples were drawn between 10:00 and 13:00 hours. 36,37 sexual intercourse. To our knowledge, no study to date has For the assessment of the local severity of PC (primary investigated the relationship between sexual function and cog- tumor staging), TNM classification and new contemporary 38,39 nitive status in men undergoing radical prostatectomy for PC. PC grading system (GRADE Groups 1–5) were used. The aim of the present study was to examine the rela- international index of erectile Function tionship between neuropsychological symptoms and clinical course in PC patients undergoing radical prostatectomy with (iieF-5) questionnaire or without adjunct therapy. The IIEF-5 self-report questionnaire is a simplified version of the IIEF. Both questionnaires are characterized by high sensitiv- Participants and methods ity and reliability in terms of the assessment of ED, irrespective Participants of underlying etiology. The IIEF-5 comprises five items. Four The cohort comprised 100 Caucasian patients with PC, who concern the prevalence and severity of ED, and one concerns underwent laparoscopic radical prostatectomy and were satisfaction with sexual intercourse. Each item is scored recruited between July 1, 2017 and June 30, 2018 from the on a 1–5 scale. Lower total scores indicate more severe ED. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al subjective assessment of erectile function goNogo test Patients were asked to rate erectile function before and after The GoNoGo test involves two reactions, symbolically surgery according to a scale of 1–5 (1, no erection possible; marked as “Go” and “NoGo”. In the “Go” reaction, the 5, no ED). participant is required to press the computer key when a green square appears on the computer screen. In the “NoGo” international consultation on reaction, the participant is required not to react (not press the incontinence Questionnaire: Urinary key) when a blue square appears on the screen. The stimuli incontinence (iciQ-Ui) (75 green and 25 blue squares) are presented in random The ICIQ-UI is a short self-report questionnaire that is used order. The GoNoGo test assesses response times under the to assess the intensity of incontinence and its impact on qual- condition of the need to trigger cognitive control and cogni- ity of life in adults. The scale consists of four questions con- tive inhibition. The number and percentage of incorrect and cerning the incidence of incontinence episodes, urine output correct “Go” and “NoGo” reactions and the response time during episodes of incontinence, and the degree to which (ms) for correct “Go” reactions are examined. The primary incontinence interferes with daily functioning (frequency of purpose of the GoNoGo test is to assess inhibitory control. urinary incontinence, amount of leakage, overall impact of Verbal memory test (VMT) and delayed urinary incontinence, self-diagnostic item). The respondent indicates the severity of the symptoms according to a multi- verbal memory test (VMDT) level scale. The test result is the sum of the scores obtained, This test comprises five consecutive stages. The researcher where the minimum score is 0 and the maximum score is 21. reads a list of ten words five times to the participant. After Higher scores indicate a greater impact on quality of life. each repetition, the participant is asked to recall the ten words in any order. The group of words read in each of the five rep - Psychological assessment etitions is constant and unchangeable. For each repetition, the The presence and severity of anxiety and depressive symp- researcher records: the number of correctly repeated words, toms were measured using the self-report Hospital Anxiety the number of intrusions (words from outside the list), and and Depression Scale (HADS). The HADS is comprised the number of perseverations (repetitions). After an interval of two parts. These generate separate scores for anxiety of 20 minutes, the participant is asked to repeat the words (HADS-A) and depression (HADS-D). Each part comprises from the original ten-item list, without having had them first seven items. For each item, the respondent is asked to select read aloud by the researcher. The test evaluates immediate one of the four answers, which are ranked in terms of symp- auditory memory (the number of words remembered), learn- tom severity. For each part, the score is calculated as the sum ing (improvement of results in subsequent repetitions), and of the responses to all seven items; the higher the score, the deferred memory (remembering repeated words). greater the severity of the reported anxiety or depression. Visual working memory test (VWMT) Neurocognitive assessment At the beginning of the test, seven covered playing cards Neurocognitive evaluation was performed using the “Neurotest” are presented on the computer screen. The cards are then computer battery. This set of neuropsychological tests enables sequentially uncovered and recovered (each card is exposed comprehensive assessment of cognitive function. The four for 2 seconds). The seven cards differ in terms of numbers individual tests are described in the following section. and figures, as in a standard deck of playing cards. The par - ticipant is required to memorize the card layout. After pre- simple reaction time (sr T) senting all seven cards, one of the previously presented cards In the SRT task, the participant is asked to respond to a is displayed at the top of the screen. The participant must stimulus presented on the computer screen. The participant indicate the previous location of the displayed card. In this must press the computer key each time a green circle appears way, all seven cards are displayed in sequence. The number on the screen. The participant is instructed to react as fast of correctly and incorrectly indicated locations is recorded. as possible. The task is preceded by a trial version, in which This test assesses spatial memory. the stimulus is presented five times. The number of correct responses and the average response time (ms) are measured. statistical analysis The SRT task measures reaction time, general alertness, and Statistica 13.1 software was used for statistical analysis. In motor speed. the first step, the Shapiro–Wilk test was used to assess the submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Jarzemski et al Dovepress normality of the distribution of study variables. Since the radical prostatectomy and adjuvant treatment (n=23). In this distribution was non-normal, nonparametric tests were used group, 15 patients underwent radiotherapy (radiotherapy was in the subsequent analyses. The Mann–Whitney U-test was started 6 weeks after the surgery and the adjunct therapy was used to calculate the statistical significance of inter-group stopped 7 months after the procedure), two received only differences and Kruskall–Willis’s ANOVA for differences hormonal treatment (androgen-deprivation therapy [ADT]), between more than three groups. The R-Spearman test was and six patients underwent both forms of adjuvant treatment. used to determine the significance of the correlations. To The demographic and clinical data of the two study subgroups facilitate inter-group comparisons, effect sizes were calcu- are shown in Table 1. No statistically significant inter-group lated using the Cohen’s d method. A p-value of ,0.05 was differences were found in terms of demographic parameters, considered statistically significant. the presence of comorbidities, or physical activity. However, postoperative ED was more prevalent in the adjuvant therapy Results subgroup (percentage of patients with 1 point on IIEF-5 scale For the purposes of the present analyses, the cohort was in the study subgroups 40% vs 61%), while no significant divided into two treatment subgroups: 1) patients undergoing differences were found in the score of IIEF results in the radical prostatectomy only (n=77) and 2) patients undergoing subgroups (Table 2). Similarly, no significant inter-group Table 1 Demographic and clinical data of the two prostate cancer therapy subgroups Parameter Total Prostatectomy Prostatectomy and Cohen’s d p-value (n=100) only (n=77) adjuvant treatment (n=23) age (years) 66.0 (60.0–70.0) 66.0 (60.0–70.0) 65.0 (60.0–71.0) 0.16 0.95 BMi (kg/m ) 27.1 (25.1–29.7) 26.7 (24.7–29.4) 27.7 (25.7–31.5) 0.36 0.11 Diabetes (n, %) 13 (13%) 11 (14%) 2 (8.5%) 0.69 hypertension (n, %) 56 (56%) 42 (54.5%) 14 (61%) 0.64 Mi (n, %) 9 (9%) 6 (9.5%) 3 (13%) 0.71 stroke (n, %) 7 (7%) 6 (9.5%) 1 (4%) 0.81 education Basic (n, %) 5 (5%) 5 (6.5%) 0 (0%) 0.85 Vocational (n, %) 28 (28%) 19 (24.5%) 9 (39%) secondary (n, %) 34 (34%) 29 (37.5%) 5 (22%) higher (n, %) 33 (33%) 24 (31.5%) 9 (39%) Physical activity None (n, %) 34 (34%) 24 (31%) 10 (43.5%) 0.34 ,1×/week (n, %) 31 (31%) 20 (26%) 11 (48%) ,3×/week 35 (35%) 33 (43%) 2 (8.5%) Nicotinism (n, %) 47 (47%) 37 (48%) 10 (43.5%) 0.74 erectile dysfunction before 6 (6%) 2 (2.5%) 4 (14%) 0.96 surgery (0/1) (n, %) erectile dysfunction after 20 (20%) 2 (2.5%) 18 (78%) 0.022 surgery (0/1) (n, %) Time from surgery (months) 19.0 (12.0–39.0) 19.0 (12.0–39.0) 17.0 (13.0–27.0) 0.15 0.67 grade group 1.0 (1.0–2.0) 1.0 (1.0–2.0) 2.0 (1.0–4.0) 1.02 0.0002 TNM classification primary tumor staging T2N0 (n, %) 1 (1%) 1 (15%) 0 (0%) 0.01 T2a (n, %) 13 (13%) 13 (16.5%) 0 (0%) T2B (n, %) 1 (1%) 0 (0%) 1 (4.5%) T2c (n, %) 64 (64%) 61 (79%) 3 (13%) T3a (n, %) 10 (10%) 0 (0%) 10 (43.5%) T3B (n, %) 8 (8%) 1 (1.5%) 7 (30%) T3c (n, %) 3 (3%) 1 (1.5%) 2 (9%) Notes: Data are shown as the median (25th–75th quartile) or number (%). inter-group differences were assessed using the Mann–Whitney U-test. effect size was measured using the Cohen’s d method. Significant p-values are shown in bold. Abbreviations: BMi, body mass index; Mi, myocardial infarction; 0/1, presence or absence of erectile dysfunction. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al Table 2 Psychological, clinical, and biochemical parameters in prostate cancer therapy subgroups Parameter (ref value) Total (n=100) Prostatectomy only Prostatectomy and Cohen’s d p-value (n=77) adjuvant treatment (n=23) haDs-anxiety 3.0 (1.0–7.0) 3.0 (1.0–6.0) 5.0 (3.0–9.0) 0.70 0.01 haDs-Depression 3.0 (1.0–6.0) 2.0 (1.0–4.0) 4.0 (2.0–8.0) 0.77 0.027 iciQ-total 3.0 (0.0–8.0) 2.0 (0.0–7.0) 7.0 (0.0–13.0) 1.1 0.045 iieF-5 0.0 (0.0–7.0) 0.0 (0.0–8.0) 0.0 (0.0–5.0) 0.61 0.31 Psa-1 ( ,4.1 ng/ml) 7.5 (5.4–10.6) 7.1 (5.2–9.3) 10.3 (6.4–17.0) 0.8 0.035 Psa-2 ( ,4.1 ng/ml) 0.003 (0.003–0.037) 0.003 (0.003–0.017) 0.008 (0.003–0.14) 0.09 0.045 Testosterone (1.23–8.92 ng/ml) 4.63 (3.15–6.26) 5.2 (3.49–6.4) 3.56 (2.47–4.5) 0.70 0.001 Notes: Data are shown as the median (25th–75th quartile). inter-group differences were assessed using the Mann–Whitney U-test. effect size was measured using the Cohen’s d method. Significant p-values are shown in bold. Abbreviations: haDs, hospital anxiety and Depression scale; iciQ, international consultation on incontinence Modular Questionnaire; iieF-5, international index of Erectile Function; PSA, prostate-specific antigen; Ref value, reference values. differences were found for the results of the neurocognitive and worse urinary outcomes. Significant inter-group dif - test battery (Table 3). For the VMDT, the finding of better ferences in biochemical results were also observed, with a results in patients from the radical prostatectomy only sub- significantly lower testosterone level and significantly higher group showed a trend toward significance. The analysis of PSA-1 and PSA-2 levels being observed in the adjuvant differences in cognitive test results between the test group therapy subgroup. and the control group showed a number of significant dif - Tables 4 and 5 show the correlations between erectile ferences to the detriment of patients with PC in the areas of function before and after surgery and demographic, clinical, VMT, VWDT, GoNoGo, and VWMT, and no significant biochemical, and neuropsychological data. Erection function differences in the SRT results were found (Figures 1–4). after the surgery correlated significantly with the number Adjuvant treatment showed a significant association of VWMT correct answers, and a trend toward statistical with higher expressed depressive and anxiety symptoms significance was observed for SRT correct answers and Table 3 cognitive test results for the prostate cancer therapy subgroups Parameter Total Prostatectomy only Prostatectomy and Cohen’s d p-value (n=100) (n=77) adjuvant treatment (n=23) srT-c 25.0 (25.0–25.0) 25.0 (25.0–25.0) 25.0 (25.0–25.0) 0.005 0.92 srT-rT (ms) 280.8 (234.3–319.1) 281.3 (234.6–316.9) 274.7 (233.3–343.9) 0.29 0.73 VM-1 5.0 (4.0–7.0) 5.0 (5.0–6.0) 5.0 (4.0–7.0) 1.52 0.60 VM-2 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 0.06 0.95 VM-3 7.0 (7.0–8.0) 7.0 (7.0–8.0) 8.0 (6.0–8.0) 0.07 0.83 VM-4 8.0 (7.0–10.0) 8.0 (6.0–10.0) 8.0 (7.0–10.0) 0.05 0.62 VM-5 8.0 (7.0–10.0) 8.0 (6.0–10.0) 8.0 (7.0–10.0) 0.05 0.64 VMDT 6.0 (5.0–7.0) 6.0 (5.0–7.0) 5.0 (4.0–7.0) 0.64 0.04 goNogo-c 74.0 (73.0–75.0) 74.0 (73.0–75.0) 74.0 (73.0–75.0) 0.10 0.90 goNogo-rT (ms) 365.8 (323.6–414.3) 366.2 (326.4–419.6) 363.1 (310.4–397.5) 0.25 0.39 goNogo incgO 1.0 (0.0–2.0) 1.0 (0.0–2.0) 1.0 (0.0–2.0) 0.28 0.89 goNogo incNogo 5.0 (2.0–8.0) 4.0 (2.0–7.0) 6.0 (3.0–9.0) 0.07 0.16 VWMT-c 5.0 (3.0–6.5) 6.0 (3.0–7.0) 5.0 (3.0–6.0) 0.09 0.64 VWMT-crT (ms) 3,150.0 (2,570.0–4,441.0) 3,219.0 (2,578.0–4,266.0) 2,828.0 (2,562.0–4,586.0) 0.28 0.76 VWMT-irT (ms) 3,499.0 (0.0–4,742.0) 3,484.0 (0.0–4,516.0) 3,515.0 (0.0–6,625.0) 0.12 0.57 Notes: Data are shown as the median (25th–75th quartile) or number (%). inter-group differences were assessed using the Mann–Whitney U-test. effect size was measured using the Cohen’s d method. Significant p-value is shown in bold. Abbreviations: srT-c, simple reaction time test (number of correct answers); srT-rT, simple reaction time test (average reaction time); VM-1 to VM-5, verbal memory (number of words remembered in each of the five attempts); VMDT, verbal delayed memory test (number of words remembered); GoNoGo-C, GoNoGo test (number of correct answers); rT, reaction time; incgo, number of incorrect go answers; incNogo, incorrect Nogo answers; VWMT-c, visual working memory test (number of correct answers); crT, average response time for correct answers; irT, average response time for incorrect answers. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Jarzemski et al Dovepress Simple reaction time test, study group vs control group 350.0 317.2 293.9 300.0 250.0 200.0 150.0 100.0 50.0 25.0 24.9 0.0 SRT-C (n) p=0.27SRT-RT (ms) p=0.33 Study group Control group Figure 1 simple reaction time test results in the study and control groups. Abbreviations: srT-c, simple reaction time test (number of correct answers); srT-rT, simple reaction time test (average reaction time). GoNoGo incorrect NoGo answers. A significant correlation The neurocognitive test results were then correlated with was also found between GoNoGo reaction time and erectile the occurrence of the most common postoperative symptoms function before surgery. Significant correlations were found (Table 6). A significant correlation was found between results between scores for HADS-A and HADS-D and erectile func- for the VMDT and both ICIQ-total and IIEF-5. Similarly, the tion after surgery. number of correct responses in the VWMT showed a signifi - The GRADE correlation analysis carried out with the cant correlation with the results of the IIEF-5. No significant results of cognitive tests and the analysis of differences in correlations were found for the remaining neurocognitive the results of patients with various grade group stages did tests. The severity of depressive and anxiety symptoms not show any significant correlations. showed a significant correlation with ICIQ. The analysis of correlations between neurocognitive test results and biochemical results revealed a significant correla - Discussion tion between worse VMDT results and a higher level of PSA The present observational clinical study analyzed the demo- before surgery (r=- 0.303, p=0.018). graphic, clinical, biochemical, and neuropsychological 9 HUEDOPHPRU\WHVWDQGYHUEDOPHPRU\GHOD\HGWHVWVWXG\JURXSYVFRQWUROJURXS 1XPEHURIUHQXPEHUHGZRUGV 90S  90S  90S  90S  90S  90'7 S 6WXG\JURXS &RQWUROJURXS Figure 2 VMT and VMDT results in the study and control groups. Abbreviations: VMT, verbal memory test; VM-1 to VM-5, verbal memory (number of words remembered in each of the five attempts); VMDT, verbal delayed memory test (number of words remembered). submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Number of correct answers and reaction time Dovepress Jarzemski et al RXSYVFRQWUROJURXS*R1R*RWHVWVWXG\JU UHDFWLRQWLPH 1XPEHURIDQVZHUVDQG *R1R*R& Q  PV *R1R*R *R1R*R,QF*2 Q *R1R*R,QF1R*R Q S  S  S S 6WXG\JURXS &RQWUROJURXS Figure 3 goNogo test results in the study and control groups. Abbreviations: goNogo-c, goNogo test (number of correct answers); rT, reaction time; incgo, number of incorrect go answers; incNogo, incorrect Nogo answers. characteristics of patients undergoing treatment for PC. The in the period immediately following treatment. A previous results indicate that personal and clinical factors determined meta-analysis demonstrated visual and spatial cognitive psychological and cognitive outcomes. The main determinant dysfunction in patients undergoing hormonal treatment for of cognitive outcome in the present cohort was therapy type, ie, PC, with no significant abnormalities being observed in other radical prostatectomy only versus radical prostatectomy with investigated cognitive domains. In the present cohort, inter- chemical and/or hormonal adjuvant therapy. The form and group differences were found for VMDT only (Table 3). No complexity of therapy was determined by the characteristics of inter-group differences were found in terms of visual or spa- the disease, whereby a more advanced clinical stage required tial cognitive processes. However, similar results for deferred the implementation of additional therapeutic methods. memory function have been reported in PC patients treated Previous research shows that oncological therapy is asso- with radiotherapy, with no major deficits being detected in ciated with deterioration in cognitive functioning, particularly terms of attention or executive function. Research in patients 9 G\JURXSYVFRQWUROJURXSLVXDOZRUNLQJPHPRU\WHVWVWX DQGUHDFWLRQWLPH 1XPEHURIFRUUHFWDQVZHUV 9:07 &S 9:07 >V@& S 6WXG\JURXS &RQWUROJURXS Figure 4 VWMT results in the study and control groups. Abbreviations: VWMT-c, visual working memory test (number of correct answers); crT, average response time for correct answers. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress 57 Jarzemski et al Dovepress Table 4 r-spearman correlations between cognitive test results Table 6 r-spearman correlations between clinical scales and and erectile function before and after surgery in all groups (n=100) cognitive test results Parameter Erection p-value Erection p-value Parameter ICIQ-total p-value IIEF-5 p-value before after VM-1 - 0.14 0.16 - 0.04 0.69 surgery surgery VM-2 - 0.10 0.32 - 0.13 0.19 srT-c - 0.018 0.85 - 0.17 0.09 VM-3 0.02 0.84 0.07 0.48 srT-rT - 0.14 0.16 - 0.16 0.11 VM-4 - 0.05 0.62 0.11 0.27 - 0.12 VM-1 0.14 0.16 0.23 VM-5 - 0.04 0.69 0.12 0.23 VM-2 0.18 0.07 - 0.15 0.13 VMDT-c - 0.23 0.02 0.35 0.006 VM-3 0.08 0.42 - 0.05 0.62 VWMT-c - 0.16 0.11 0.29 0.003 VM-4 0.09 0.37 0.02 0.84 VWMT-crT 0.16 0.11 0.02 0.84 VM-5 0.09 0.37 0.03 0.76 VWMT-irT 0.02 0.84 0.17 0.09 VMDT-c 0.12 0.23 0.12 0.23 haDs-anxiety 0.23 0.02 - 0.22 0.02 goNogo-c - 0.04 0.69 0.09 0.37 goNogo-rT - 0.21 0.03 0.03 0.76 ha Ds-Depression 0.38 0.00009 - 0.13 0.19 goNogo 0.04 0.69 - 0.09 0.37 Note: Significant p-values are shown in bold. Abbreviations: haDs, hospital anxiety and Depression scale; iciQ, international incgO consultation on incontinence Modular Questionnaire; iieF-5, international index of goNogo - 0.05 0.62 - 0.17 0.09 erectile Function; VM-1 to VM-5, verbal memory correct answers (number of words incNogo remembered in each of the five attempts); VMDT-C, verbal delayed memory test correct answer (number of words remembered); VWMT-c, visual working memory VWMT-c - 0.03 0.76 0.27 0.006 test (number of correct answers); crT, average response time for correct answers; VWMT-crT 0.05 0.62 0.03 0.76 irT, average response time for incorrect answers. VWMT-irT - 0.05 0.62 - 0.13 0.13 Note: Significant p-values are shown in bold. Abbreviations: srT-c, simple reaction time test (number of correct answers); with atrial fibrillation shows that delayed memory dysfunc - srT-rT, simple reaction time test (average reaction time); VM-1 to VM-5, verbal memory (number of words remembered in each of the five attempts); VMDT-C, tion is associated with a more advanced disease state. verbal delayed memory test correct answers (number of words remembered); Further analyses showed that patients in the (more aggres- goNogo-c, goNogo test (number of correct answers); rT, reaction time; incgo, number of incorrect go answers; incNogo, incorrect Nogo answers; VWMT-c, sive) adjunct therapy subgroup displayed more severe anxiety visual working memory test (number of correct answers); crT, average response and depressive symptoms (Table 2). These symptoms are time for correct answers; irT, average response time for incorrect answers. recognized risk factors for cognitive decline. However, no significant association was found in the present cohort Table 5 r-spearman correlations between demographic, clinical, psychological, and biochemical factors and erectile function between the severity of anxiety and depression and scores before and after surgery in all groups (n=100) in the neurocognitive test battery. Research suggests that the Parameter Erection p-value Erection p-value occurrence of psychological disorders, in particular anxiety before after and depression, secondary to oncological treatment for PC is surgery surgery associated with poorer global functioning, and thus requires age (years) - 0.22 0.027 - 0.23 0.02 17,45 appropriate treatment. BMi (kg/m ) - 0.05 0.62 - 0.29 0.003 Subsequent analyses in the present cohort concerned Time from – – 0.28 0.004 the relationship between neuropsychological parameters surgery (months) and biochemical parameters of PC. Analysis of individual Psa pre-surgery 0.05 0.62 - 0.11 0.27 (ng/ml) determinants of disease severity confirmed significant cor - Psa post-surgery - 0.08 0.42 - 0.21 0.03 relations between worse VMDT results and a higher level (ng/ml) of PSA before surgery (r=- 0.303, p=0.018). The latter is Psa actual – – - 0.05 0.62 associated with a more advanced disease state. By contrast, (ng/ml) lower testosterone levels showed no association with worse Testosterone – – 0.23 0.02 actual (ng/ml) cognitive performance, more severe symptoms of anxiety haDs-a – – - 0.23 0.02 and depression, or subjective assessment of erection quality haDs-D – – - 0.20 0.045 (Table 5). Previous data on the relationship between cognitive Note: Significant p-values are shown in bold. status and testosterone levels in older men undergoing treat- Abbreviations: haDs, hospital anxiety and Depression scale; BMi, body mass index; PSA, prostate-specific antigen. ment for PC are equivocal. Salminem et al found correlations submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al between low testosterone levels and deterioration in psycho- the relevance of psychological symptoms, for predicting motor speed, slowed reaction time in some attention tests, and clinical course following treatment for PC. impairments in delayed recall and letter recognition speed. Limitations Research suggests that the primary determinant of cogni- The results and conclusions of this study are mainly limited tive dysfunction in the context of PC treatment and reduced 47,48 by a small group of respondents. In addition, single assess- testosterone levels is ADT. However, some studies have ment of patients at different times after surgery makes found no effect of ADT on cognitive functioning. Other drawing unambiguous conclusions difficult. reports suggest that the emergence of cognitive dysfunction following ADT therapy for PC is attributable to other fac- Conclusion tors, for example, genetic susceptibility. In neuroimaging Patients undergoing both surgical and adjunct therapy for studies, ADT has been found to reduce the amount of gray PC are at risk of cognitive dysfunction and symptoms of matter in the anterior cortex, dorsolateral prefrontal cortex, anxiety and depression. The present data suggest that the and primary motor cortex. However, a meta-analysis clinical course of postoperative psychological disorder is conducted in 2016 concluded that no clear evidence is yet determined by clinical disease stage and treatment method. available concerning either the mechanism or the nature of Physical complications of treatment are associated with a postoperative cognitive dysfunction in patients undergoing decrease in quality of life and delayed memory dysfunction. hormonal treatment for PC. Furthermore, this study has proven that fewer complications Another important aspect of the present study was the after surgery are associated with better psychological and analysis of the physical consequences of treatment. For this cognitive functioning. Appropriate neuropsychological and purpose, two issues were examined: 1) the impact of urinary psychiatric care can improve compliance and quality of life incontinence on quality of life and 2) subjective and objec- among patients after prostatectomy. In addition, adequate tive evaluation of erection quality. These complications are care and treatment for ED and urinary incontinence may associated with a high psychological burden and a reduction translate into clinical improvement. in quality of life. Analysis of erection quality, as assessed subjectively on a scale of 1–5, revealed no inter-group dif- Acknowledgments ferences. Available studies suggest that ED occurs in up to The authors received no external funding for the conduct of 89% of patients following treatment for PC. These results the present research. correspond to those obtained in the present adjunct therapy subgroup. These patients were also characterized by a sig- Disclosure nificantly higher PSA level before and after surgery and a The authors report no conflicts of interest in this work. significantly lower postoperative testosterone level compared with patients undergoing surgical treatment only (Table 2). References Analysis of correlations between the cognitive tests, the 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J HADS, and the ICIQ-total indicated a significant correlation Clin. 2018;68(1):7–30. doi:10.3322/caac.21442 2. Lehto US, Tenhola H, Taari K, Aromaa A. Patients’ perceptions of the between the results for delayed memory and ICIQ scores negative effects following different prostate cancer treatments and the (Table 6). A significant association was found between worse impact on psychological well-being: a nationwide survey. Br J Cancer. ICIQ parameters and more severe anxiety and depressive 2017;116(7):864–873. doi:10.1038/bjc.2017.30 3. Maguire R, Hanly P, Drummond FJ, Gavin A, Sharp L. Expecting the symptoms. Urinary continence is an important aspect of worst? The relationship between retrospective and prospective appraisals quality of life in this population. Research has shown that of illness on quality of life in prostate cancer survivors. Psychooncology. 2018;27(4):1237–1243. around 40% of patients rate their quality of life as signifi - 4. Taylor KL, Luta G, Hoffman RM, et al. Quality of life among men cantly decreased following treatment for PC, and that this with low-risk prostate cancer during the first year following diagnosis: is impacted by therapy type. However, a study of patients the PREPARE prospective cohort study. Transl Behav Med. 2018;8: 156–165. doi:10.1093/tbm/ibx005 from Nordic countries suggests that the highest percentage of 5. Sanda MG1, Dunn RL, Michalski J, et al. Quality of life and satisfaction dissatisfaction with quality of life is found among untreated with outcome among prostate-cancer survivors. N Engl J Med. 2008; 358(12):1250–1261. doi:10.1056/NEJMoa074311 PC patients. 6. Clark JA, Inui TS, Silliman RA, et al. Patients’ perceptions of quality The present results indicate the value of both deferred of life after treatment for early prostate cancer. J Clin Oncol. 2003; memory parameters in combination with disease stage and 21(20):3777–3784. doi:10.1200/JCO.2003.02.115 submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Jarzemski et al Dovepress 7. Jang JW, Drumm MR, Efstathiou JA, et al. Long-term quality of life 25. Frey AU, Sønksen J, Fode M. Neglected side effects after radical after den fi itive treatment for prostate cancer: patient-reported outcomes prostatectomy: a systematic review. J Sex Med. 2014;11(2):374–385. in the second posttreatment decade. Cancer Med. 2017;6(7):1827–1836. doi:10.1111/jsm.12403 doi:10.1002/cam4.1103 26. Tran S, Boissier R, Perrin J, Karsenty G, Lechevallier E. Review of the 8. Prostate Cancer Treatment (PDQ ). Health professional version. PDQ different treatments and management for prostate cancer and fertility. cancer information summaries [Internet]. PDQ Adult Treatment Edi- Urology. 2015;86(5):936–941. doi:10.1016/j.urology.2015.07.010 torial Board. Available from: https://www.ncbi.nlm.nih.gov/books/ 27. Chambers SK, Chung E, Wittert G, Hyde MK. Erectile dysfunction, NBK66036. Accessed February 6, 2018. masculinity, and psychosocial outcomes: a review of the experiences 9. Kong EH, Deatrick JA, Bradway CK. Men’s experiences after prosta- of men after prostate cancer treatment. Transl Androl Urol. 2017;6(1): tectomy: a meta-synthesis. Int J Nurs Stud. 2017;74:162–171. doi:10. 60–68. doi:10.21037/tau.2016.08.12 1016/j.ijnurstu.2017.07.013 28. Zaider T, Manne S, Nelson C, Mulhall J, Kissane D. Loss of mas- 10. Sharpley CF, Christie DRH, Bitsika V, et al. Neurobiological and culine identity, marital affection, and sexual bother in men with psychological evidence of chronic stress in prostate cancer patients. localized prostate cancer. J Sex Med. 2012;9(10):2724–2732. doi:10. Eur J Cancer Care (Engl). 2017;26:6. doi:10.1111/ecc.12671 1111/j.1743-6109.2012.02897.x 11. Perez MA, Meyerowitz BE, Lieskovsky G, Skinner DG, Reynolds B, 29. Bokhour BG, Clark JA, Inui TS, Silliman RA, Talcott JA. Sexuality Skinner EC. Quality of life and sexuality following radical prostatec- after treatment for early prostate cancer: exploring the meanings of tomy in patients with prostate cancer who use or do not use erectile “erectile dysfunction”. J Gen Intern Med. 2001;16(10):649–655. aids. Urology. 1997;50(5):740–746. doi:10.1016/S0090-4295(97) 30. Gannon K, Guerro-Blanco M, Patel A, Abel P. Re-constructing mascu- 00327-0 linity following radical prostatectomy for prostate cancer. Aging Male. 12. Koike H, Kohjimoto Y, Iba A, et al. Health-related quality of life after 2010;13(4):258–264. doi:10.3109/13685538.2010.487554 robot-assisted radical prostatectomy compared with laparoscopic radi- 31. Meyer JP, Gillatt DA, Lockyer R, Macdonagh R. The effect of erectile cal prostatectomy. J Robot Surg. 2017;11(3):325–331. doi:10.1007/ dysfunction on the quality of life of men after radical prostatectomy. s11701-016-0659-8 BJU Int. 2003;92(9):929–931. 13. Gershman B, Psutka SP, McGovern FJ, et al. Patient-reported functional 32. Wennick A, Jönsson AK, Bratt O, Stenzelius K. Everyday life after outcomes following open, laparoscopic, and robotic assisted radical a radical prostatectomy – a qualitative study of men under 65 years prostatectomy performed by high-volume surgeons at high-volume of age. Eur J Oncol Nurs. 2017;30:107–112. doi:10.1016/j.ejon. hospitals. Eur Urol Focus. 2016;2(2):172–179. doi:10.1016/j.euf. 2017.08.008 2015.06.011 33. Morote J, Tabernero ÁJ, Álvarez-Ossorio JL, et al; Grupo de inves- 14. Trofimenko V, Myers JB, Brant WO. Post-prostatectomy incontinence: tigación ANAMEM. Cognitive function in patients on androgen how common and bothersome is it really? Sex Med Rev. 2017;5(4): suppression: A prospective, multicentric study. Actas Urol Esp. 2018; 536–543. doi:10.1016/j.sxmr.2017.05.001 42(2):114–120. doi: 10.1016/j.acuro.2017.04.007. 15. Couper JW, Love AW, Dunai JV, et al. The psychological aftermath of 34. Mundell NL, Daly RM, Macpherson H, Fraser SF. Cognitive decline in prostate cancer treatment choices: a comparison of depression, anxiety prostate cancer patients undergoing ADT: a potential role for exercise and quality of life outcomes over the 12 months following diagnosis. training. Endocr Relat Cancer. 2017;24(4):R145–R155. doi:10.1530/ Med J Aust. 2009;190(7 Suppl):S86–S89. ERC-16-0493 16. Pastore AL, Mir A, Maruccia S, et al. Psychological distress in patients 35. Gunlusoy B, Ceylan Y, Koskderelioglu A, et al. Cognitive effects of undergoing surgery for urological cancer: a single centre cross-sectional androgen deprivation therapy in men with advanced prostate cancer. study. Urol Oncol. 2017;35(12):673.e1–673.e7. doi:10.1016/j.urolonc. Urology. 2017;103:167–172. doi:10.1016/j.urology.2016.12.060 2017.08.006 36. Wright H, Jenks RA, Demeyere N. Frequent Sexual Activity Predicts 17. Meissner VH, Herkommer K, Marten-Mittag B, Gschwend JE, Dinkel A. Specific Cognitive Abilities in Older Adults. J Gerontol B Psychol Sci Prostate cancer-related anxiety in long-term survivors after radical Soc Sci. 2019;74(1):47–51. doi: 10.1093/geronb/gbx065. prostatectomy. J Cancer Surviv. 2017;11(6):800–807. doi:10.1007/ 37. Wright H, Jenks RA. Sex on the brain! Associations between sexual s11764-017-0619-y activity and cognitive function in older age. Age Ageing. 2016;45(2): 18. McConkey RW. The psychosocial dimensions of fatigue in men treated 313–317. doi:10.1093/ageing/afv197 for prostate cancer. Int J Urol Nurs. 2016;10(1):37–43. doi:10.1111/ 38. Cheng L, Montironi R, Bostwick DG, Lopez-Beltran A, Berney DM. ijun.12089 Staging of prostate cancer. Histopathology. 2012;60(1):87–117. doi:10. 19. Köhler N, Gansera L, Holze S, et al. Cancer-related fatigue in patients 1111/j.1365-2559.2011.04025.x before and after radical prostatectomy. Results of a prospective multi centre 39. Epstein JI. A new contemporary prostate cancer grading system. study. Support Care Cancer. 2014;22(11):2883–2889. doi:10.1007/ Ann Pathol. 2015;35(6):474–476. doi:10.1016/j.annpat.2015.09.00 s00520-014-2265-5 40. Zuniga KE, Bishop NJ. Recent cancer treatment and memory decline 20. Boeri L, Capogrosso P, Ventimiglia E, et al. Depressive symptoms and in older adults: an analysis of the 2002–2012 Health and Retirement low sexual desire after radical prostatectomy: early and long-term out- Study. J Geriatr Oncol. 2018;9(3):186–193. comes in a real-life setting. J Urol. 2018;199(2):474–480. doi:10.1016/j. 41. McGinty HL, Phillips KM, Jim HS, et al. Cognitive functioning in juro.2017.08.104 men receiving androgen deprivation therapy for prostate cancer: a 21. Punnen S, Cowan JE, Dunn LB, Shumay DM, Carroll PR, systematic review and meta-analysis. Support Care Cancer. 2014;22(8): Cooperberg MR. A longitudinal study of anxiety, depression and 2271–2280. doi:10.1007/s00520-014-2285-1 distress as predictors of sexual and urinary quality of life in men with 42. Feng LR, Espina A, Saligan LN. Association of fatigue intensification prostate cancer. BJU Int. 2013;112(2):E67–E75. doi:10.1111/bju.12209 with cognitive impairment during radiation therapy for prostate cancer. 22. Fode M, Serefoglu EC, Albersen M, Sønksen J. Sexuality following Oncology. 2018;94:363–372. doi:10.1159/000487081 radical prostatectomy: is restoration of erectile function enough? 43. Mietła B, Budzyński J, Bieliński M, Mieczkowski A, Pulkowska-Ulg fi J, Sex Med Rev. 2017;5(1):110–119. doi:10.1016/j.sxmr.2016.07.005 Borkowska A. Links between parameters of long-term latent memory 23. Clavell-Hernández J, Martin C, Wang R. Orgasmic dysfunction follow- and progression from paroxysmal to permanent atrial fibrillation during ing radical prostatectomy: review of current literature. Sex Med Rev. a five-year observation period. A preliminary study. Kardiol Pol. 2016; 2018;6(1):124–134. doi:10.1016/j.sxmr.2017.09.003 74(8):754–776. 24. Kadono Y, Machioka K, Nakashima K, et al. Changes in penile length 44. de Vito A, Calamia M, Greening S, Roye S. The association of anxiety, after radical prostatectomy: investigation of the underlying anatomical depression, and worry symptoms on cognitive performance in older adults. mechanism. BJU Int. 2017;120(2):293–299. doi:10.1111/bju.13777 Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2017;20:1–13. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al 45. Watts S, Leydon G, Birch B, et al. Depression and anxiety in prostate 50. Gonzalez BD, Jim HS, Booth-Jones M, et al. Course and predictors of cancer: a systematic review and meta-analysis of prevalence rates. BMJ cognitive function in patients with prostate cancer receiving androgen- Open. 2014;4(3):e003901. doi:10.1136/bmjopen-2013-003901 deprivation therapy: a controlled comparison. J Clin Oncol. 2015;33(18): 46. Salminen EK, Portin RI, Koskinen A, Helenius H, Nurmi M. Associa- 2021–2027. doi:10.1200/JCO.2014.60.1963 tions between serum testosterone fall and cognitive function in prostate 51. Chao HH, Hu S, Ide JS, et al. Effects of androgen deprivation on cere- cancer patients. Clin Cancer Res. 2004;10(22):7575–7582. doi:10. bral morphometry in prostate cancer patients – an exploratory study. 1158/1078-0432.CCR-04-0750 PLoS One. 2013;8(8):e72032. doi:10.1371/journal.pone.0072032 47. Wu LM, Tanenbaum ML, Dijkers MP, et al. Cognitive and neurobehav- 52. Hua JT, Hildreth KL, Pelak VS. Effects of testosterone therapy on ioral symptoms in patients with non-metastatic prostate cancer treated cognitive function in aging: a systematic review. Cogn Behav Neurol. with androgen deprivation therapy or observation: a mixed methods study. 2016;29(3):122–138. doi:10.1097/WNN.0000000000000104 Soc Sci Med. 2016;156:80–89. doi:10.1016/j.socscimed.2016.03.016 53. Chappidi MR, Kates M, Sopko NA, et al. Erectile dysfunction treatment 48. Nelson CJ, Lee JS, Gamboa MC, Roth AJ. Cognitive effects of hormone following radical cystoprostatectomy: analysis of a nationwide insur- therapy in men with prostate cancer: a review. Cancer. 2008;113(5): ance claims database. J Sex Med. 2017;14(6):810–817. doi:10.1016/j. 1097–1106. doi:10.1002/cncr.23658 jsxm.2017.04.002 49. Chao HH, Uchio E, Zhang S, et al. Effects of androgen deprivation 54. Fosså SD, Bengtsson T, Borre M, Ahlgren G, Rannikko A, Dahl AA. on brain function in prostate cancer patients – a prospective observa- Reduction of quality of life in prostate cancer patients: experience among tional cohort analysis. BMC Cancer. 2012;12:37. doi:10.1186/1471- 6200 men in the Nordic countries. Scand J Urol. 2016;50(5):330–337. 2407-12-371 doi:10.1080/21681805.2016.1201859 Neuropsychiatric Disease and Treatment Dovepress Publish your work in this journal Neuropsychiatric Disease and Treatment is an international, peer- and is the official journal of The International Neuropsychiatric reviewed journal of clinical therapeutics and pharmacology focusing Association (INA). The manuscript management system is completely on concise rapid reporting of clinical or pre-clinical studies on a online and includes a very quick and fair peer-review system, which range of neuropsychiatric and neurological disorders. This journal is all easy to use. 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Cognitive function, depression, and anxiety in patients undergoing radical prostatectomy with and without adjuvant treatment

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Journal name: Neuropsychiatric Disease and Treatment Article Designation: Original Research Year: 2019 Volume: 15 Running head verso: Jarzemski et al Neuropsychiatric Disease and Treatment Dovepress Running head recto: Jarzemski et al open access to scientific and medical research DOI: 200501 Open Access Full Text Article O rig i N al r esearch cognitive function, depression, and anxiety in patients undergoing radical prostatectomy with and without adjuvant treatment This article was published in the following Dove Medical Press journal: Neuropsychiatric Disease and Treatment Piotr Jarzemski Background: Prostate cancer (PC) is one of the most common malignant tumors in developed countries. Both PC and treatment for PC have an adverse impact on physical and mental well- Bartosz Brzoszczyk being, and are associated with decreased quality of life. The aim of the present study was to Alicja Popiołek examine the relationship between neuropsychological symptoms and clinical course in PC agnieszka patients undergoing radical prostatectomy with or without adjunct therapy. Stachowicz-Karpińska Methods: The cohort comprised 100 patients aged 50–77 years who underwent radical, Szymon Gołota laparoscopic prostatectomy for PC. Twenty-three patients with a more advanced clinical Maciej Bieliński stage also received adjuvant therapy (radiotherapy and hormonotherapy). Clinical evaluation alina Borkowska included self-report assessment, physical examination, and biochemical tests (testosterone and Department of laparoscopic, prostate-specific antigen). In addition, the presence and intensity of sexual dysfunction, urinary general, and Oncological Urology, dysfunction, anxiety-depressive symptoms, and cognitive dysfunction were assessed. Jan Biziel University hospital No 2, Bydgoszcz, Poland; Department of Results: The group of patients undergoing complex therapy was characterized by a significantly clinical Neuropsychology, Nicolaus worse result of deferred memory ( p=0.04). A significant correlation was found between post- Copernicus University in Toruń, surgery erectile function and scores for the visual working memory test (correct answers; collegium Medicum, Bydgoszcz, Poland VWMT-C; p=0.006) and Hospital Anxiety and Depression Scale depression ( p=0.045) and anxiety scores ( p=0.02). A trend toward significance was also observed for simple reaction time (correct answers; p=0.09). A significant correlation was found between results for the delayed verbal memory test and all physical symptoms (International Consultation on Incon- tinence Questionnaire-total, p=0.02; International Index of Erectile Function-5, p=0.006). Similarly, a significant correlation was found between the VWMT-C and score for sexual dysfunction ( p=0.003). Conclusion: Patients undergoing both surgical and adjunct therapy for PC are at risk for psychological burden and cognitive disorders. In the present cohort, physical complications of therapy were associated with depression, anxiety, and delayed memory dysfunction. Further- more, this study has proven that fewer complications after surgery are associated with better psychological and cognitive functioning. Appropriate neuropsychological and psychiatric care can improve compliance and quality of life among patients after prostatectomy. Keywords: prostate cancer, cognition, anxiety, depression, sexual dysfunction Introduction Correspondence: Maciej Bieliński Prostate cancer (PC) is one of the most common malignancies in developed countries. Department of clinical Neuropsychology, According to the American Cancer Society, among men in the US, PC is the most Nicolaus Copernicus University in Toruń, collegium Medicum, ul. Marii curie- frequently diagnosed malignant tumor and the second leading cause of cancer death Skłodowskiej 9, 85-094 Bydgoszcz, Poland (after lung cancer). Both PC and treatment for PC have a negative impact on physical Tel/fax +4 852 585 3703 2–7 email bielinskim@gmail.com and mental well-being, and are associated with decreased quality of life. PC is often submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 819–829 Dovepress © 2019 Jarzemski et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/NDT.s200501 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Jarzemski et al Dovepress diagnosed after presentation with disease-related physical urological outpatient department of the Jan Biziel University symptoms, and is frequently associated with anxiety con- Hospital No 2 in Bydgoszcz, Poland. The median age of 8–10 cerning treatment and its possible consequences. Primary the participants was 66 years (range: 50–77 years). Patients therapy for PC remains surgical radical prostatectomy. Over were evaluated once postoperatively, after an average of recent decades, numerous studies of PC have demonstrated 27 months (minimum after 3 and a maximum of 102). A a significant association between treatment method and the medical history was obtained and, if indicated, tests were 11–13 incidence of complications. All forms of surgical treat- performed to identify comorbid common diseases that have ment are associated with periprocedural and deferred com- an impact on cognitive function (diabetes, hypertension, plications, which impact both the physical and psychological previous myocardial infarction, and stroke). Patients with 2,13 aspects of quality of life. either a psychiatric disorder or addiction to illicit drugs or The most commonly reported postoperative physical symp- alcohol were excluded, as categorized by the Diagnostic 11,14 toms are sexual dysfunction and difficulties with micturition. and Statistical Manual of Mental Disorders, 4th edition, as The most common postoperative psychological symptoms were those with any neurological abnormality. The study 15–17 18,19 15,16,20 are anxiety, chronic fatigue, and depression. was approved by the Bioethical Commission of the Nicolaus Research has demonstrated an association between specific Copernicus University, Collegium Medicum in Bydgoszcz psychological symptoms and the prevalence and severity (Approval No 476/2017). All participants provided written of sexual and urinary outcomes in the PC population. informed consent prior to inclusion. All study procedures The most common forms of deterioration in sexual func- were performed in accordance with the principles of the tion in PC patients are erectile dysfunction (ED), difficulties Declaration of Helsinki. A control group, including 112 men in experiencing orgasm, shortening and/or deformation of (aged 48–76 years and matched to age, p=0.44), with no sig- 24,25 26 20 the penis, fertility disorders, and reduced sex drive. nificant somatic and mental diseases and in a stable clinical These symptoms are associated with a reduced sense of mas- condition for at least 6 months, was selected as a reference 27–30 culinity and physical attractiveness. Research shows that for the results of Neurotest. PC patients with treatment-related ED often blame themselves clinical Pc staging and biochemical for their postoperative sexual and relationship difficulties, and for their inability to meet the sexual needs of their measures partners. This is also the case for disorders of self-image Prior to surgery, clinical PC stage was assessed via mea- and self-confidence, which may also interfere with personal surement of prostate-specific antigen (PSA) and magnetic 29,32 relationships, in particular relationships with their partners. resonance imaging of the prostate. At follow-up, besides Research in PC patients has also demonstrated a signifi - complementary treatment, first (6 weeks post-surgery) and cant deterioration in cognitive function. Several studies have the actual PSA results were analyzed. In the adjunct therapy demonstrated that cognitive dysfunction in this population is subgroup, biochemical failure was defined as a 6-week PSA associated with hormonal disorders, including those arising as level of .0.2 ng/mL. Free testosterone was measured at 33–35 a result of hormonal therapy. In older adults from the non- 6-week postoperative follow-up using an electrochemilu- PC population, better scores for cognitive functioning have minescence immumoassay technique. All testosterone blood been associated with sexual satisfaction and the frequency of samples were drawn between 10:00 and 13:00 hours. 36,37 sexual intercourse. To our knowledge, no study to date has For the assessment of the local severity of PC (primary investigated the relationship between sexual function and cog- tumor staging), TNM classification and new contemporary 38,39 nitive status in men undergoing radical prostatectomy for PC. PC grading system (GRADE Groups 1–5) were used. The aim of the present study was to examine the rela- international index of erectile Function tionship between neuropsychological symptoms and clinical course in PC patients undergoing radical prostatectomy with (iieF-5) questionnaire or without adjunct therapy. The IIEF-5 self-report questionnaire is a simplified version of the IIEF. Both questionnaires are characterized by high sensitiv- Participants and methods ity and reliability in terms of the assessment of ED, irrespective Participants of underlying etiology. The IIEF-5 comprises five items. Four The cohort comprised 100 Caucasian patients with PC, who concern the prevalence and severity of ED, and one concerns underwent laparoscopic radical prostatectomy and were satisfaction with sexual intercourse. Each item is scored recruited between July 1, 2017 and June 30, 2018 from the on a 1–5 scale. Lower total scores indicate more severe ED. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al subjective assessment of erectile function goNogo test Patients were asked to rate erectile function before and after The GoNoGo test involves two reactions, symbolically surgery according to a scale of 1–5 (1, no erection possible; marked as “Go” and “NoGo”. In the “Go” reaction, the 5, no ED). participant is required to press the computer key when a green square appears on the computer screen. In the “NoGo” international consultation on reaction, the participant is required not to react (not press the incontinence Questionnaire: Urinary key) when a blue square appears on the screen. The stimuli incontinence (iciQ-Ui) (75 green and 25 blue squares) are presented in random The ICIQ-UI is a short self-report questionnaire that is used order. The GoNoGo test assesses response times under the to assess the intensity of incontinence and its impact on qual- condition of the need to trigger cognitive control and cogni- ity of life in adults. The scale consists of four questions con- tive inhibition. The number and percentage of incorrect and cerning the incidence of incontinence episodes, urine output correct “Go” and “NoGo” reactions and the response time during episodes of incontinence, and the degree to which (ms) for correct “Go” reactions are examined. The primary incontinence interferes with daily functioning (frequency of purpose of the GoNoGo test is to assess inhibitory control. urinary incontinence, amount of leakage, overall impact of Verbal memory test (VMT) and delayed urinary incontinence, self-diagnostic item). The respondent indicates the severity of the symptoms according to a multi- verbal memory test (VMDT) level scale. The test result is the sum of the scores obtained, This test comprises five consecutive stages. The researcher where the minimum score is 0 and the maximum score is 21. reads a list of ten words five times to the participant. After Higher scores indicate a greater impact on quality of life. each repetition, the participant is asked to recall the ten words in any order. The group of words read in each of the five rep - Psychological assessment etitions is constant and unchangeable. For each repetition, the The presence and severity of anxiety and depressive symp- researcher records: the number of correctly repeated words, toms were measured using the self-report Hospital Anxiety the number of intrusions (words from outside the list), and and Depression Scale (HADS). The HADS is comprised the number of perseverations (repetitions). After an interval of two parts. These generate separate scores for anxiety of 20 minutes, the participant is asked to repeat the words (HADS-A) and depression (HADS-D). Each part comprises from the original ten-item list, without having had them first seven items. For each item, the respondent is asked to select read aloud by the researcher. The test evaluates immediate one of the four answers, which are ranked in terms of symp- auditory memory (the number of words remembered), learn- tom severity. For each part, the score is calculated as the sum ing (improvement of results in subsequent repetitions), and of the responses to all seven items; the higher the score, the deferred memory (remembering repeated words). greater the severity of the reported anxiety or depression. Visual working memory test (VWMT) Neurocognitive assessment At the beginning of the test, seven covered playing cards Neurocognitive evaluation was performed using the “Neurotest” are presented on the computer screen. The cards are then computer battery. This set of neuropsychological tests enables sequentially uncovered and recovered (each card is exposed comprehensive assessment of cognitive function. The four for 2 seconds). The seven cards differ in terms of numbers individual tests are described in the following section. and figures, as in a standard deck of playing cards. The par - ticipant is required to memorize the card layout. After pre- simple reaction time (sr T) senting all seven cards, one of the previously presented cards In the SRT task, the participant is asked to respond to a is displayed at the top of the screen. The participant must stimulus presented on the computer screen. The participant indicate the previous location of the displayed card. In this must press the computer key each time a green circle appears way, all seven cards are displayed in sequence. The number on the screen. The participant is instructed to react as fast of correctly and incorrectly indicated locations is recorded. as possible. The task is preceded by a trial version, in which This test assesses spatial memory. the stimulus is presented five times. The number of correct responses and the average response time (ms) are measured. statistical analysis The SRT task measures reaction time, general alertness, and Statistica 13.1 software was used for statistical analysis. In motor speed. the first step, the Shapiro–Wilk test was used to assess the submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Jarzemski et al Dovepress normality of the distribution of study variables. Since the radical prostatectomy and adjuvant treatment (n=23). In this distribution was non-normal, nonparametric tests were used group, 15 patients underwent radiotherapy (radiotherapy was in the subsequent analyses. The Mann–Whitney U-test was started 6 weeks after the surgery and the adjunct therapy was used to calculate the statistical significance of inter-group stopped 7 months after the procedure), two received only differences and Kruskall–Willis’s ANOVA for differences hormonal treatment (androgen-deprivation therapy [ADT]), between more than three groups. The R-Spearman test was and six patients underwent both forms of adjuvant treatment. used to determine the significance of the correlations. To The demographic and clinical data of the two study subgroups facilitate inter-group comparisons, effect sizes were calcu- are shown in Table 1. No statistically significant inter-group lated using the Cohen’s d method. A p-value of ,0.05 was differences were found in terms of demographic parameters, considered statistically significant. the presence of comorbidities, or physical activity. However, postoperative ED was more prevalent in the adjuvant therapy Results subgroup (percentage of patients with 1 point on IIEF-5 scale For the purposes of the present analyses, the cohort was in the study subgroups 40% vs 61%), while no significant divided into two treatment subgroups: 1) patients undergoing differences were found in the score of IIEF results in the radical prostatectomy only (n=77) and 2) patients undergoing subgroups (Table 2). Similarly, no significant inter-group Table 1 Demographic and clinical data of the two prostate cancer therapy subgroups Parameter Total Prostatectomy Prostatectomy and Cohen’s d p-value (n=100) only (n=77) adjuvant treatment (n=23) age (years) 66.0 (60.0–70.0) 66.0 (60.0–70.0) 65.0 (60.0–71.0) 0.16 0.95 BMi (kg/m ) 27.1 (25.1–29.7) 26.7 (24.7–29.4) 27.7 (25.7–31.5) 0.36 0.11 Diabetes (n, %) 13 (13%) 11 (14%) 2 (8.5%) 0.69 hypertension (n, %) 56 (56%) 42 (54.5%) 14 (61%) 0.64 Mi (n, %) 9 (9%) 6 (9.5%) 3 (13%) 0.71 stroke (n, %) 7 (7%) 6 (9.5%) 1 (4%) 0.81 education Basic (n, %) 5 (5%) 5 (6.5%) 0 (0%) 0.85 Vocational (n, %) 28 (28%) 19 (24.5%) 9 (39%) secondary (n, %) 34 (34%) 29 (37.5%) 5 (22%) higher (n, %) 33 (33%) 24 (31.5%) 9 (39%) Physical activity None (n, %) 34 (34%) 24 (31%) 10 (43.5%) 0.34 ,1×/week (n, %) 31 (31%) 20 (26%) 11 (48%) ,3×/week 35 (35%) 33 (43%) 2 (8.5%) Nicotinism (n, %) 47 (47%) 37 (48%) 10 (43.5%) 0.74 erectile dysfunction before 6 (6%) 2 (2.5%) 4 (14%) 0.96 surgery (0/1) (n, %) erectile dysfunction after 20 (20%) 2 (2.5%) 18 (78%) 0.022 surgery (0/1) (n, %) Time from surgery (months) 19.0 (12.0–39.0) 19.0 (12.0–39.0) 17.0 (13.0–27.0) 0.15 0.67 grade group 1.0 (1.0–2.0) 1.0 (1.0–2.0) 2.0 (1.0–4.0) 1.02 0.0002 TNM classification primary tumor staging T2N0 (n, %) 1 (1%) 1 (15%) 0 (0%) 0.01 T2a (n, %) 13 (13%) 13 (16.5%) 0 (0%) T2B (n, %) 1 (1%) 0 (0%) 1 (4.5%) T2c (n, %) 64 (64%) 61 (79%) 3 (13%) T3a (n, %) 10 (10%) 0 (0%) 10 (43.5%) T3B (n, %) 8 (8%) 1 (1.5%) 7 (30%) T3c (n, %) 3 (3%) 1 (1.5%) 2 (9%) Notes: Data are shown as the median (25th–75th quartile) or number (%). inter-group differences were assessed using the Mann–Whitney U-test. effect size was measured using the Cohen’s d method. Significant p-values are shown in bold. Abbreviations: BMi, body mass index; Mi, myocardial infarction; 0/1, presence or absence of erectile dysfunction. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al Table 2 Psychological, clinical, and biochemical parameters in prostate cancer therapy subgroups Parameter (ref value) Total (n=100) Prostatectomy only Prostatectomy and Cohen’s d p-value (n=77) adjuvant treatment (n=23) haDs-anxiety 3.0 (1.0–7.0) 3.0 (1.0–6.0) 5.0 (3.0–9.0) 0.70 0.01 haDs-Depression 3.0 (1.0–6.0) 2.0 (1.0–4.0) 4.0 (2.0–8.0) 0.77 0.027 iciQ-total 3.0 (0.0–8.0) 2.0 (0.0–7.0) 7.0 (0.0–13.0) 1.1 0.045 iieF-5 0.0 (0.0–7.0) 0.0 (0.0–8.0) 0.0 (0.0–5.0) 0.61 0.31 Psa-1 ( ,4.1 ng/ml) 7.5 (5.4–10.6) 7.1 (5.2–9.3) 10.3 (6.4–17.0) 0.8 0.035 Psa-2 ( ,4.1 ng/ml) 0.003 (0.003–0.037) 0.003 (0.003–0.017) 0.008 (0.003–0.14) 0.09 0.045 Testosterone (1.23–8.92 ng/ml) 4.63 (3.15–6.26) 5.2 (3.49–6.4) 3.56 (2.47–4.5) 0.70 0.001 Notes: Data are shown as the median (25th–75th quartile). inter-group differences were assessed using the Mann–Whitney U-test. effect size was measured using the Cohen’s d method. Significant p-values are shown in bold. Abbreviations: haDs, hospital anxiety and Depression scale; iciQ, international consultation on incontinence Modular Questionnaire; iieF-5, international index of Erectile Function; PSA, prostate-specific antigen; Ref value, reference values. differences were found for the results of the neurocognitive and worse urinary outcomes. Significant inter-group dif - test battery (Table 3). For the VMDT, the finding of better ferences in biochemical results were also observed, with a results in patients from the radical prostatectomy only sub- significantly lower testosterone level and significantly higher group showed a trend toward significance. The analysis of PSA-1 and PSA-2 levels being observed in the adjuvant differences in cognitive test results between the test group therapy subgroup. and the control group showed a number of significant dif - Tables 4 and 5 show the correlations between erectile ferences to the detriment of patients with PC in the areas of function before and after surgery and demographic, clinical, VMT, VWDT, GoNoGo, and VWMT, and no significant biochemical, and neuropsychological data. Erection function differences in the SRT results were found (Figures 1–4). after the surgery correlated significantly with the number Adjuvant treatment showed a significant association of VWMT correct answers, and a trend toward statistical with higher expressed depressive and anxiety symptoms significance was observed for SRT correct answers and Table 3 cognitive test results for the prostate cancer therapy subgroups Parameter Total Prostatectomy only Prostatectomy and Cohen’s d p-value (n=100) (n=77) adjuvant treatment (n=23) srT-c 25.0 (25.0–25.0) 25.0 (25.0–25.0) 25.0 (25.0–25.0) 0.005 0.92 srT-rT (ms) 280.8 (234.3–319.1) 281.3 (234.6–316.9) 274.7 (233.3–343.9) 0.29 0.73 VM-1 5.0 (4.0–7.0) 5.0 (5.0–6.0) 5.0 (4.0–7.0) 1.52 0.60 VM-2 7.0 (6.0–8.0) 7.0 (6.0–8.0) 7.0 (6.0–8.0) 0.06 0.95 VM-3 7.0 (7.0–8.0) 7.0 (7.0–8.0) 8.0 (6.0–8.0) 0.07 0.83 VM-4 8.0 (7.0–10.0) 8.0 (6.0–10.0) 8.0 (7.0–10.0) 0.05 0.62 VM-5 8.0 (7.0–10.0) 8.0 (6.0–10.0) 8.0 (7.0–10.0) 0.05 0.64 VMDT 6.0 (5.0–7.0) 6.0 (5.0–7.0) 5.0 (4.0–7.0) 0.64 0.04 goNogo-c 74.0 (73.0–75.0) 74.0 (73.0–75.0) 74.0 (73.0–75.0) 0.10 0.90 goNogo-rT (ms) 365.8 (323.6–414.3) 366.2 (326.4–419.6) 363.1 (310.4–397.5) 0.25 0.39 goNogo incgO 1.0 (0.0–2.0) 1.0 (0.0–2.0) 1.0 (0.0–2.0) 0.28 0.89 goNogo incNogo 5.0 (2.0–8.0) 4.0 (2.0–7.0) 6.0 (3.0–9.0) 0.07 0.16 VWMT-c 5.0 (3.0–6.5) 6.0 (3.0–7.0) 5.0 (3.0–6.0) 0.09 0.64 VWMT-crT (ms) 3,150.0 (2,570.0–4,441.0) 3,219.0 (2,578.0–4,266.0) 2,828.0 (2,562.0–4,586.0) 0.28 0.76 VWMT-irT (ms) 3,499.0 (0.0–4,742.0) 3,484.0 (0.0–4,516.0) 3,515.0 (0.0–6,625.0) 0.12 0.57 Notes: Data are shown as the median (25th–75th quartile) or number (%). inter-group differences were assessed using the Mann–Whitney U-test. effect size was measured using the Cohen’s d method. Significant p-value is shown in bold. Abbreviations: srT-c, simple reaction time test (number of correct answers); srT-rT, simple reaction time test (average reaction time); VM-1 to VM-5, verbal memory (number of words remembered in each of the five attempts); VMDT, verbal delayed memory test (number of words remembered); GoNoGo-C, GoNoGo test (number of correct answers); rT, reaction time; incgo, number of incorrect go answers; incNogo, incorrect Nogo answers; VWMT-c, visual working memory test (number of correct answers); crT, average response time for correct answers; irT, average response time for incorrect answers. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Jarzemski et al Dovepress Simple reaction time test, study group vs control group 350.0 317.2 293.9 300.0 250.0 200.0 150.0 100.0 50.0 25.0 24.9 0.0 SRT-C (n) p=0.27SRT-RT (ms) p=0.33 Study group Control group Figure 1 simple reaction time test results in the study and control groups. Abbreviations: srT-c, simple reaction time test (number of correct answers); srT-rT, simple reaction time test (average reaction time). GoNoGo incorrect NoGo answers. A significant correlation The neurocognitive test results were then correlated with was also found between GoNoGo reaction time and erectile the occurrence of the most common postoperative symptoms function before surgery. Significant correlations were found (Table 6). A significant correlation was found between results between scores for HADS-A and HADS-D and erectile func- for the VMDT and both ICIQ-total and IIEF-5. Similarly, the tion after surgery. number of correct responses in the VWMT showed a signifi - The GRADE correlation analysis carried out with the cant correlation with the results of the IIEF-5. No significant results of cognitive tests and the analysis of differences in correlations were found for the remaining neurocognitive the results of patients with various grade group stages did tests. The severity of depressive and anxiety symptoms not show any significant correlations. showed a significant correlation with ICIQ. The analysis of correlations between neurocognitive test results and biochemical results revealed a significant correla - Discussion tion between worse VMDT results and a higher level of PSA The present observational clinical study analyzed the demo- before surgery (r=- 0.303, p=0.018). graphic, clinical, biochemical, and neuropsychological 9 HUEDOPHPRU\WHVWDQGYHUEDOPHPRU\GHOD\HGWHVWVWXG\JURXSYVFRQWUROJURXS 1XPEHURIUHQXPEHUHGZRUGV 90S  90S  90S  90S  90S  90'7 S 6WXG\JURXS &RQWUROJURXS Figure 2 VMT and VMDT results in the study and control groups. Abbreviations: VMT, verbal memory test; VM-1 to VM-5, verbal memory (number of words remembered in each of the five attempts); VMDT, verbal delayed memory test (number of words remembered). submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Number of correct answers and reaction time Dovepress Jarzemski et al RXSYVFRQWUROJURXS*R1R*RWHVWVWXG\JU UHDFWLRQWLPH 1XPEHURIDQVZHUVDQG *R1R*R& Q  PV *R1R*R *R1R*R,QF*2 Q *R1R*R,QF1R*R Q S  S  S S 6WXG\JURXS &RQWUROJURXS Figure 3 goNogo test results in the study and control groups. Abbreviations: goNogo-c, goNogo test (number of correct answers); rT, reaction time; incgo, number of incorrect go answers; incNogo, incorrect Nogo answers. characteristics of patients undergoing treatment for PC. The in the period immediately following treatment. A previous results indicate that personal and clinical factors determined meta-analysis demonstrated visual and spatial cognitive psychological and cognitive outcomes. The main determinant dysfunction in patients undergoing hormonal treatment for of cognitive outcome in the present cohort was therapy type, ie, PC, with no significant abnormalities being observed in other radical prostatectomy only versus radical prostatectomy with investigated cognitive domains. In the present cohort, inter- chemical and/or hormonal adjuvant therapy. The form and group differences were found for VMDT only (Table 3). No complexity of therapy was determined by the characteristics of inter-group differences were found in terms of visual or spa- the disease, whereby a more advanced clinical stage required tial cognitive processes. However, similar results for deferred the implementation of additional therapeutic methods. memory function have been reported in PC patients treated Previous research shows that oncological therapy is asso- with radiotherapy, with no major deficits being detected in ciated with deterioration in cognitive functioning, particularly terms of attention or executive function. Research in patients 9 G\JURXSYVFRQWUROJURXSLVXDOZRUNLQJPHPRU\WHVWVWX DQGUHDFWLRQWLPH 1XPEHURIFRUUHFWDQVZHUV 9:07 &S 9:07 >V@& S 6WXG\JURXS &RQWUROJURXS Figure 4 VWMT results in the study and control groups. Abbreviations: VWMT-c, visual working memory test (number of correct answers); crT, average response time for correct answers. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress 57 Jarzemski et al Dovepress Table 4 r-spearman correlations between cognitive test results Table 6 r-spearman correlations between clinical scales and and erectile function before and after surgery in all groups (n=100) cognitive test results Parameter Erection p-value Erection p-value Parameter ICIQ-total p-value IIEF-5 p-value before after VM-1 - 0.14 0.16 - 0.04 0.69 surgery surgery VM-2 - 0.10 0.32 - 0.13 0.19 srT-c - 0.018 0.85 - 0.17 0.09 VM-3 0.02 0.84 0.07 0.48 srT-rT - 0.14 0.16 - 0.16 0.11 VM-4 - 0.05 0.62 0.11 0.27 - 0.12 VM-1 0.14 0.16 0.23 VM-5 - 0.04 0.69 0.12 0.23 VM-2 0.18 0.07 - 0.15 0.13 VMDT-c - 0.23 0.02 0.35 0.006 VM-3 0.08 0.42 - 0.05 0.62 VWMT-c - 0.16 0.11 0.29 0.003 VM-4 0.09 0.37 0.02 0.84 VWMT-crT 0.16 0.11 0.02 0.84 VM-5 0.09 0.37 0.03 0.76 VWMT-irT 0.02 0.84 0.17 0.09 VMDT-c 0.12 0.23 0.12 0.23 haDs-anxiety 0.23 0.02 - 0.22 0.02 goNogo-c - 0.04 0.69 0.09 0.37 goNogo-rT - 0.21 0.03 0.03 0.76 ha Ds-Depression 0.38 0.00009 - 0.13 0.19 goNogo 0.04 0.69 - 0.09 0.37 Note: Significant p-values are shown in bold. Abbreviations: haDs, hospital anxiety and Depression scale; iciQ, international incgO consultation on incontinence Modular Questionnaire; iieF-5, international index of goNogo - 0.05 0.62 - 0.17 0.09 erectile Function; VM-1 to VM-5, verbal memory correct answers (number of words incNogo remembered in each of the five attempts); VMDT-C, verbal delayed memory test correct answer (number of words remembered); VWMT-c, visual working memory VWMT-c - 0.03 0.76 0.27 0.006 test (number of correct answers); crT, average response time for correct answers; VWMT-crT 0.05 0.62 0.03 0.76 irT, average response time for incorrect answers. VWMT-irT - 0.05 0.62 - 0.13 0.13 Note: Significant p-values are shown in bold. Abbreviations: srT-c, simple reaction time test (number of correct answers); with atrial fibrillation shows that delayed memory dysfunc - srT-rT, simple reaction time test (average reaction time); VM-1 to VM-5, verbal memory (number of words remembered in each of the five attempts); VMDT-C, tion is associated with a more advanced disease state. verbal delayed memory test correct answers (number of words remembered); Further analyses showed that patients in the (more aggres- goNogo-c, goNogo test (number of correct answers); rT, reaction time; incgo, number of incorrect go answers; incNogo, incorrect Nogo answers; VWMT-c, sive) adjunct therapy subgroup displayed more severe anxiety visual working memory test (number of correct answers); crT, average response and depressive symptoms (Table 2). These symptoms are time for correct answers; irT, average response time for incorrect answers. recognized risk factors for cognitive decline. However, no significant association was found in the present cohort Table 5 r-spearman correlations between demographic, clinical, psychological, and biochemical factors and erectile function between the severity of anxiety and depression and scores before and after surgery in all groups (n=100) in the neurocognitive test battery. Research suggests that the Parameter Erection p-value Erection p-value occurrence of psychological disorders, in particular anxiety before after and depression, secondary to oncological treatment for PC is surgery surgery associated with poorer global functioning, and thus requires age (years) - 0.22 0.027 - 0.23 0.02 17,45 appropriate treatment. BMi (kg/m ) - 0.05 0.62 - 0.29 0.003 Subsequent analyses in the present cohort concerned Time from – – 0.28 0.004 the relationship between neuropsychological parameters surgery (months) and biochemical parameters of PC. Analysis of individual Psa pre-surgery 0.05 0.62 - 0.11 0.27 (ng/ml) determinants of disease severity confirmed significant cor - Psa post-surgery - 0.08 0.42 - 0.21 0.03 relations between worse VMDT results and a higher level (ng/ml) of PSA before surgery (r=- 0.303, p=0.018). The latter is Psa actual – – - 0.05 0.62 associated with a more advanced disease state. By contrast, (ng/ml) lower testosterone levels showed no association with worse Testosterone – – 0.23 0.02 actual (ng/ml) cognitive performance, more severe symptoms of anxiety haDs-a – – - 0.23 0.02 and depression, or subjective assessment of erection quality haDs-D – – - 0.20 0.045 (Table 5). Previous data on the relationship between cognitive Note: Significant p-values are shown in bold. status and testosterone levels in older men undergoing treat- Abbreviations: haDs, hospital anxiety and Depression scale; BMi, body mass index; PSA, prostate-specific antigen. ment for PC are equivocal. Salminem et al found correlations submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al between low testosterone levels and deterioration in psycho- the relevance of psychological symptoms, for predicting motor speed, slowed reaction time in some attention tests, and clinical course following treatment for PC. impairments in delayed recall and letter recognition speed. Limitations Research suggests that the primary determinant of cogni- The results and conclusions of this study are mainly limited tive dysfunction in the context of PC treatment and reduced 47,48 by a small group of respondents. In addition, single assess- testosterone levels is ADT. However, some studies have ment of patients at different times after surgery makes found no effect of ADT on cognitive functioning. Other drawing unambiguous conclusions difficult. reports suggest that the emergence of cognitive dysfunction following ADT therapy for PC is attributable to other fac- Conclusion tors, for example, genetic susceptibility. In neuroimaging Patients undergoing both surgical and adjunct therapy for studies, ADT has been found to reduce the amount of gray PC are at risk of cognitive dysfunction and symptoms of matter in the anterior cortex, dorsolateral prefrontal cortex, anxiety and depression. The present data suggest that the and primary motor cortex. However, a meta-analysis clinical course of postoperative psychological disorder is conducted in 2016 concluded that no clear evidence is yet determined by clinical disease stage and treatment method. available concerning either the mechanism or the nature of Physical complications of treatment are associated with a postoperative cognitive dysfunction in patients undergoing decrease in quality of life and delayed memory dysfunction. hormonal treatment for PC. Furthermore, this study has proven that fewer complications Another important aspect of the present study was the after surgery are associated with better psychological and analysis of the physical consequences of treatment. For this cognitive functioning. Appropriate neuropsychological and purpose, two issues were examined: 1) the impact of urinary psychiatric care can improve compliance and quality of life incontinence on quality of life and 2) subjective and objec- among patients after prostatectomy. In addition, adequate tive evaluation of erection quality. These complications are care and treatment for ED and urinary incontinence may associated with a high psychological burden and a reduction translate into clinical improvement. in quality of life. Analysis of erection quality, as assessed subjectively on a scale of 1–5, revealed no inter-group dif- Acknowledgments ferences. Available studies suggest that ED occurs in up to The authors received no external funding for the conduct of 89% of patients following treatment for PC. These results the present research. correspond to those obtained in the present adjunct therapy subgroup. These patients were also characterized by a sig- Disclosure nificantly higher PSA level before and after surgery and a The authors report no conflicts of interest in this work. significantly lower postoperative testosterone level compared with patients undergoing surgical treatment only (Table 2). References Analysis of correlations between the cognitive tests, the 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J HADS, and the ICIQ-total indicated a significant correlation Clin. 2018;68(1):7–30. doi:10.3322/caac.21442 2. Lehto US, Tenhola H, Taari K, Aromaa A. Patients’ perceptions of the between the results for delayed memory and ICIQ scores negative effects following different prostate cancer treatments and the (Table 6). A significant association was found between worse impact on psychological well-being: a nationwide survey. Br J Cancer. ICIQ parameters and more severe anxiety and depressive 2017;116(7):864–873. doi:10.1038/bjc.2017.30 3. Maguire R, Hanly P, Drummond FJ, Gavin A, Sharp L. Expecting the symptoms. Urinary continence is an important aspect of worst? The relationship between retrospective and prospective appraisals quality of life in this population. Research has shown that of illness on quality of life in prostate cancer survivors. Psychooncology. 2018;27(4):1237–1243. around 40% of patients rate their quality of life as signifi - 4. Taylor KL, Luta G, Hoffman RM, et al. Quality of life among men cantly decreased following treatment for PC, and that this with low-risk prostate cancer during the first year following diagnosis: is impacted by therapy type. However, a study of patients the PREPARE prospective cohort study. Transl Behav Med. 2018;8: 156–165. doi:10.1093/tbm/ibx005 from Nordic countries suggests that the highest percentage of 5. Sanda MG1, Dunn RL, Michalski J, et al. Quality of life and satisfaction dissatisfaction with quality of life is found among untreated with outcome among prostate-cancer survivors. N Engl J Med. 2008; 358(12):1250–1261. doi:10.1056/NEJMoa074311 PC patients. 6. Clark JA, Inui TS, Silliman RA, et al. Patients’ perceptions of quality The present results indicate the value of both deferred of life after treatment for early prostate cancer. J Clin Oncol. 2003; memory parameters in combination with disease stage and 21(20):3777–3784. doi:10.1200/JCO.2003.02.115 submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Jarzemski et al Dovepress 7. Jang JW, Drumm MR, Efstathiou JA, et al. Long-term quality of life 25. Frey AU, Sønksen J, Fode M. Neglected side effects after radical after den fi itive treatment for prostate cancer: patient-reported outcomes prostatectomy: a systematic review. J Sex Med. 2014;11(2):374–385. in the second posttreatment decade. Cancer Med. 2017;6(7):1827–1836. doi:10.1111/jsm.12403 doi:10.1002/cam4.1103 26. Tran S, Boissier R, Perrin J, Karsenty G, Lechevallier E. Review of the 8. Prostate Cancer Treatment (PDQ ). Health professional version. PDQ different treatments and management for prostate cancer and fertility. cancer information summaries [Internet]. PDQ Adult Treatment Edi- Urology. 2015;86(5):936–941. doi:10.1016/j.urology.2015.07.010 torial Board. Available from: https://www.ncbi.nlm.nih.gov/books/ 27. Chambers SK, Chung E, Wittert G, Hyde MK. Erectile dysfunction, NBK66036. Accessed February 6, 2018. masculinity, and psychosocial outcomes: a review of the experiences 9. Kong EH, Deatrick JA, Bradway CK. Men’s experiences after prosta- of men after prostate cancer treatment. Transl Androl Urol. 2017;6(1): tectomy: a meta-synthesis. Int J Nurs Stud. 2017;74:162–171. doi:10. 60–68. doi:10.21037/tau.2016.08.12 1016/j.ijnurstu.2017.07.013 28. Zaider T, Manne S, Nelson C, Mulhall J, Kissane D. Loss of mas- 10. Sharpley CF, Christie DRH, Bitsika V, et al. Neurobiological and culine identity, marital affection, and sexual bother in men with psychological evidence of chronic stress in prostate cancer patients. localized prostate cancer. J Sex Med. 2012;9(10):2724–2732. doi:10. Eur J Cancer Care (Engl). 2017;26:6. doi:10.1111/ecc.12671 1111/j.1743-6109.2012.02897.x 11. Perez MA, Meyerowitz BE, Lieskovsky G, Skinner DG, Reynolds B, 29. Bokhour BG, Clark JA, Inui TS, Silliman RA, Talcott JA. Sexuality Skinner EC. Quality of life and sexuality following radical prostatec- after treatment for early prostate cancer: exploring the meanings of tomy in patients with prostate cancer who use or do not use erectile “erectile dysfunction”. J Gen Intern Med. 2001;16(10):649–655. aids. Urology. 1997;50(5):740–746. doi:10.1016/S0090-4295(97) 30. Gannon K, Guerro-Blanco M, Patel A, Abel P. Re-constructing mascu- 00327-0 linity following radical prostatectomy for prostate cancer. Aging Male. 12. Koike H, Kohjimoto Y, Iba A, et al. Health-related quality of life after 2010;13(4):258–264. doi:10.3109/13685538.2010.487554 robot-assisted radical prostatectomy compared with laparoscopic radi- 31. Meyer JP, Gillatt DA, Lockyer R, Macdonagh R. The effect of erectile cal prostatectomy. J Robot Surg. 2017;11(3):325–331. doi:10.1007/ dysfunction on the quality of life of men after radical prostatectomy. s11701-016-0659-8 BJU Int. 2003;92(9):929–931. 13. Gershman B, Psutka SP, McGovern FJ, et al. Patient-reported functional 32. Wennick A, Jönsson AK, Bratt O, Stenzelius K. Everyday life after outcomes following open, laparoscopic, and robotic assisted radical a radical prostatectomy – a qualitative study of men under 65 years prostatectomy performed by high-volume surgeons at high-volume of age. Eur J Oncol Nurs. 2017;30:107–112. doi:10.1016/j.ejon. hospitals. Eur Urol Focus. 2016;2(2):172–179. doi:10.1016/j.euf. 2017.08.008 2015.06.011 33. Morote J, Tabernero ÁJ, Álvarez-Ossorio JL, et al; Grupo de inves- 14. Trofimenko V, Myers JB, Brant WO. Post-prostatectomy incontinence: tigación ANAMEM. Cognitive function in patients on androgen how common and bothersome is it really? Sex Med Rev. 2017;5(4): suppression: A prospective, multicentric study. Actas Urol Esp. 2018; 536–543. doi:10.1016/j.sxmr.2017.05.001 42(2):114–120. doi: 10.1016/j.acuro.2017.04.007. 15. Couper JW, Love AW, Dunai JV, et al. The psychological aftermath of 34. Mundell NL, Daly RM, Macpherson H, Fraser SF. Cognitive decline in prostate cancer treatment choices: a comparison of depression, anxiety prostate cancer patients undergoing ADT: a potential role for exercise and quality of life outcomes over the 12 months following diagnosis. training. Endocr Relat Cancer. 2017;24(4):R145–R155. doi:10.1530/ Med J Aust. 2009;190(7 Suppl):S86–S89. ERC-16-0493 16. Pastore AL, Mir A, Maruccia S, et al. Psychological distress in patients 35. Gunlusoy B, Ceylan Y, Koskderelioglu A, et al. Cognitive effects of undergoing surgery for urological cancer: a single centre cross-sectional androgen deprivation therapy in men with advanced prostate cancer. study. Urol Oncol. 2017;35(12):673.e1–673.e7. doi:10.1016/j.urolonc. Urology. 2017;103:167–172. doi:10.1016/j.urology.2016.12.060 2017.08.006 36. Wright H, Jenks RA, Demeyere N. Frequent Sexual Activity Predicts 17. Meissner VH, Herkommer K, Marten-Mittag B, Gschwend JE, Dinkel A. Specific Cognitive Abilities in Older Adults. J Gerontol B Psychol Sci Prostate cancer-related anxiety in long-term survivors after radical Soc Sci. 2019;74(1):47–51. doi: 10.1093/geronb/gbx065. prostatectomy. J Cancer Surviv. 2017;11(6):800–807. doi:10.1007/ 37. Wright H, Jenks RA. Sex on the brain! Associations between sexual s11764-017-0619-y activity and cognitive function in older age. Age Ageing. 2016;45(2): 18. McConkey RW. The psychosocial dimensions of fatigue in men treated 313–317. doi:10.1093/ageing/afv197 for prostate cancer. Int J Urol Nurs. 2016;10(1):37–43. doi:10.1111/ 38. Cheng L, Montironi R, Bostwick DG, Lopez-Beltran A, Berney DM. ijun.12089 Staging of prostate cancer. Histopathology. 2012;60(1):87–117. doi:10. 19. Köhler N, Gansera L, Holze S, et al. Cancer-related fatigue in patients 1111/j.1365-2559.2011.04025.x before and after radical prostatectomy. Results of a prospective multi centre 39. Epstein JI. A new contemporary prostate cancer grading system. study. Support Care Cancer. 2014;22(11):2883–2889. doi:10.1007/ Ann Pathol. 2015;35(6):474–476. doi:10.1016/j.annpat.2015.09.00 s00520-014-2265-5 40. Zuniga KE, Bishop NJ. Recent cancer treatment and memory decline 20. Boeri L, Capogrosso P, Ventimiglia E, et al. Depressive symptoms and in older adults: an analysis of the 2002–2012 Health and Retirement low sexual desire after radical prostatectomy: early and long-term out- Study. J Geriatr Oncol. 2018;9(3):186–193. comes in a real-life setting. J Urol. 2018;199(2):474–480. doi:10.1016/j. 41. McGinty HL, Phillips KM, Jim HS, et al. Cognitive functioning in juro.2017.08.104 men receiving androgen deprivation therapy for prostate cancer: a 21. Punnen S, Cowan JE, Dunn LB, Shumay DM, Carroll PR, systematic review and meta-analysis. Support Care Cancer. 2014;22(8): Cooperberg MR. A longitudinal study of anxiety, depression and 2271–2280. doi:10.1007/s00520-014-2285-1 distress as predictors of sexual and urinary quality of life in men with 42. Feng LR, Espina A, Saligan LN. Association of fatigue intensification prostate cancer. BJU Int. 2013;112(2):E67–E75. doi:10.1111/bju.12209 with cognitive impairment during radiation therapy for prostate cancer. 22. Fode M, Serefoglu EC, Albersen M, Sønksen J. Sexuality following Oncology. 2018;94:363–372. doi:10.1159/000487081 radical prostatectomy: is restoration of erectile function enough? 43. Mietła B, Budzyński J, Bieliński M, Mieczkowski A, Pulkowska-Ulg fi J, Sex Med Rev. 2017;5(1):110–119. doi:10.1016/j.sxmr.2016.07.005 Borkowska A. Links between parameters of long-term latent memory 23. Clavell-Hernández J, Martin C, Wang R. Orgasmic dysfunction follow- and progression from paroxysmal to permanent atrial fibrillation during ing radical prostatectomy: review of current literature. Sex Med Rev. a five-year observation period. A preliminary study. Kardiol Pol. 2016; 2018;6(1):124–134. doi:10.1016/j.sxmr.2017.09.003 74(8):754–776. 24. Kadono Y, Machioka K, Nakashima K, et al. Changes in penile length 44. de Vito A, Calamia M, Greening S, Roye S. The association of anxiety, after radical prostatectomy: investigation of the underlying anatomical depression, and worry symptoms on cognitive performance in older adults. mechanism. BJU Int. 2017;120(2):293–299. doi:10.1111/bju.13777 Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2017;20:1–13. submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2019:15 Dovepress Dovepress Jarzemski et al 45. Watts S, Leydon G, Birch B, et al. Depression and anxiety in prostate 50. Gonzalez BD, Jim HS, Booth-Jones M, et al. Course and predictors of cancer: a systematic review and meta-analysis of prevalence rates. BMJ cognitive function in patients with prostate cancer receiving androgen- Open. 2014;4(3):e003901. doi:10.1136/bmjopen-2013-003901 deprivation therapy: a controlled comparison. J Clin Oncol. 2015;33(18): 46. Salminen EK, Portin RI, Koskinen A, Helenius H, Nurmi M. Associa- 2021–2027. doi:10.1200/JCO.2014.60.1963 tions between serum testosterone fall and cognitive function in prostate 51. Chao HH, Hu S, Ide JS, et al. Effects of androgen deprivation on cere- cancer patients. Clin Cancer Res. 2004;10(22):7575–7582. doi:10. bral morphometry in prostate cancer patients – an exploratory study. 1158/1078-0432.CCR-04-0750 PLoS One. 2013;8(8):e72032. doi:10.1371/journal.pone.0072032 47. Wu LM, Tanenbaum ML, Dijkers MP, et al. Cognitive and neurobehav- 52. Hua JT, Hildreth KL, Pelak VS. Effects of testosterone therapy on ioral symptoms in patients with non-metastatic prostate cancer treated cognitive function in aging: a systematic review. Cogn Behav Neurol. with androgen deprivation therapy or observation: a mixed methods study. 2016;29(3):122–138. doi:10.1097/WNN.0000000000000104 Soc Sci Med. 2016;156:80–89. doi:10.1016/j.socscimed.2016.03.016 53. Chappidi MR, Kates M, Sopko NA, et al. Erectile dysfunction treatment 48. Nelson CJ, Lee JS, Gamboa MC, Roth AJ. Cognitive effects of hormone following radical cystoprostatectomy: analysis of a nationwide insur- therapy in men with prostate cancer: a review. Cancer. 2008;113(5): ance claims database. J Sex Med. 2017;14(6):810–817. doi:10.1016/j. 1097–1106. doi:10.1002/cncr.23658 jsxm.2017.04.002 49. Chao HH, Uchio E, Zhang S, et al. Effects of androgen deprivation 54. Fosså SD, Bengtsson T, Borre M, Ahlgren G, Rannikko A, Dahl AA. on brain function in prostate cancer patients – a prospective observa- Reduction of quality of life in prostate cancer patients: experience among tional cohort analysis. BMC Cancer. 2012;12:37. doi:10.1186/1471- 6200 men in the Nordic countries. Scand J Urol. 2016;50(5):330–337. 2407-12-371 doi:10.1080/21681805.2016.1201859 Neuropsychiatric Disease and Treatment Dovepress Publish your work in this journal Neuropsychiatric Disease and Treatment is an international, peer- and is the official journal of The International Neuropsychiatric reviewed journal of clinical therapeutics and pharmacology focusing Association (INA). The manuscript management system is completely on concise rapid reporting of clinical or pre-clinical studies on a online and includes a very quick and fair peer-review system, which range of neuropsychiatric and neurological disorders. This journal is all easy to use. 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